TY - JOUR AU - Reissland, M.* AU - Hartmann, O.* AU - Tauch, S.* AU - Bugter, J.M.* AU - Prieto-Garcia, C.* AU - Schulte, C.* AU - Loebbert, S.* AU - Solvie, D.* AU - Bitman-Lotan, E.* AU - Narain, A.* AU - Jacomin, A.C.* AU - Schuelein-Voelk, C.* AU - Fuss, C.T.* AU - Pahor, N.* AU - Ade, C.* AU - Buck, V.* AU - Potente, M.* AU - Li, V.* AU - Beliu, G.* AU - Wiegering, A.* AU - Grossmann, T.* AU - Eilers, M.* AU - Wolf, E.* AU - Maric, H.* AU - Rosenfeldt, M.* AU - Maurice, M.M.* AU - Dikic, I.* AU - Gallant, P.* AU - Orian, A.* AU - Diefenbacher, M. C1 - 73157 C2 - 56937 TI - Correction: USP10 drives cancer stemness and enables super-competitor signalling in colorectal cancer. JO - Oncogene VL - 44 IS - 5 PY - 2025 SN - 0950-9232 ER - TY - JOUR AB - Editorial Expression of Concern to: Oncogenehttps://doi.org/10.1038/sj.onc.1210666, published online 16 July 2007 The Editors-in-Chief would like to alert readers that concerns have been raised regarding some of the western blot data presented in figures included in this article, specifically: Fig. 1a CADO and CEM-TR a-Tubulin blots appear highly similar. Fig. 1a J-TR Casp-8 MTX+ band appears highly similar to Fig. 2e J-TR Casp-8 MTX 72h. Fig. 1a CEM-TR and CADO Casp-8 MTX+ bands appear highly similar to Fig. 5c Casp-8 Control group (also treated with MTX) in the same cell lines. Figs. 3 and 5c CADO Casp-8 and a-Tubulin blots appear highly similar. Fig. 1a CADO and CEM-TR a-Tubulin blots appear highly similar. Fig. 1a J-TR Casp-8 MTX+ band appears highly similar to Fig. 2e J-TR Casp-8 MTX 72h. Fig. 1a CEM-TR and CADO Casp-8 MTX+ bands appear highly similar to Fig. 5c Casp-8 Control group (also treated with MTX) in the same cell lines. Figs. 3 and 5c CADO Casp-8 and a-Tubulin blots appear highly similar. The authors have stated that the possible duplications were unintentional and confirmed that the issues raised do not affect the results and conclusions of the article. The original data are no longer available due to the age of the article (16 years), in line with rules of the German Research Foundation. Readers are therefore advised to interpret these figures with caution. H Ehrhardt, K-M Debatin and I Jeremias agree to this Editorial Expression of Concern. S Fulda does not agree to this Editorial Expression of Concern. A Borkhardt has not responded to any correspondence from the editor or publisher about this Editorial Expression of Concern. The publisher has not been able to obtain current email addresses for S Häcker, S Wittmann, M Maurer and A Toloczko. AU - Ehrhardt, H.* AU - Häcker, S.* AU - Wittmann, S.* AU - Maurer, M.* AU - Borkhardt, A.* AU - Toloczko, A. AU - Debatin, K.M.* AU - Fulda, S.* AU - Jeremias, I. C1 - 71108 C2 - 55934 TI - Editorial Expression of Concern: Cytotoxic drug-induced, p53-mediated upregulation of caspase-8 in tumor cells (Oncogene, (2008), 27, 6, (783-793), 10.1038/sj.onc.1210666). JO - Oncogene PY - 2024 SN - 0950-9232 ER - TY - JOUR AB - The contribution of deubiquitylating enzymes (DUBs) to β-Catenin stabilization in intestinal stem cells and colorectal cancer (CRC) is poorly understood. Here, and by using an unbiassed screen, we discovered that the DUB USP10 stabilizes β-Catenin specifically in APC-truncated CRC in vitro and in vivo. Mechanistic studies, including in vitro binding together with computational modelling, revealed that USP10 binding to β-Catenin is mediated via the unstructured N-terminus of USP10 and is outcompeted by intact APC, favouring β-catenin degradation. However, in APC-truncated cancer cells USP10 binds to β-catenin, increasing its stability which is critical for maintaining an undifferentiated tumour identity. Elimination of USP10 reduces the expression of WNT and stem cell signatures and induces the expression of differentiation genes. Remarkably, silencing of USP10 in murine and patient-derived CRC organoids established that it is essential for NOTUM signalling and the APC super competitor-phenotype, reducing tumorigenic properties of APC-truncated CRC. These findings are clinically relevant as patient-derived organoids are highly dependent on USP10, and abundance of USP10 correlates with poorer prognosis of CRC patients. Our findings reveal, therefore, a role for USP10 in CRC cell identity, stemness, and tumorigenic growth by stabilising β-Catenin, leading to aberrant WNT signalling and degradation resistant tumours. Thus, USP10 emerges as a unique therapeutic target in APC truncated CRC. AU - Reissland, M.* AU - Hartmann, O.* AU - Tauch, S.* AU - Bugter, J.M.* AU - Prieto-Garcia, C.* AU - Schulte, C.* AU - Loebbert, S.* AU - Solvie, D.* AU - Bitman-Lotan, E.* AU - Narain, A.* AU - Jacomin, A.C.* AU - Schuelein-Voelk, C.* AU - Fuss, C.T.* AU - Pahor, N.* AU - Ade, C.* AU - Buck, V.* AU - Potente, M.* AU - Li, V.* AU - Beliu, G.* AU - Wiegering, A.* AU - Grossmann, T.* AU - Eilers, M.* AU - Wolf, E.* AU - Maric, H.* AU - Rosenfeldt, M.* AU - Maurice, M.M.* AU - Dikic, I.* AU - Gallant, P.* AU - Orian, A.* AU - Diefenbacher, M. C1 - 72141 C2 - 56503 TI - USP10 drives cancer stemness and enables super-competitor signalling in colorectal cancer. JO - Oncogene PY - 2024 SN - 0950-9232 ER - TY - JOUR AB - Metastatic tumour progression is facilitated by tumour associated macrophages (TAMs) that enforce pro-tumour mechanisms and suppress immunity. In pulmonary metastases, it is unclear whether TAMs comprise tissue resident or infiltrating, recruited macrophages; and the different expression patterns of these TAMs are not well established. Using the mouse melanoma B16F10 model of experimental pulmonary metastasis, we show that infiltrating macrophages (IM) change their gene expression from an early pro-inflammatory to a later tumour promoting profile as the lesions grow. In contrast, resident alveolar macrophages (AM) maintain expression of crucial pro-inflammatory/anti-tumour genes with time. During metastatic growth, the pool of macrophages, which initially contains mainly alveolar macrophages, increasingly consists of infiltrating macrophages potentially facilitating metastasis progression. Blocking chemokine receptor mediated macrophage infiltration in the lung revealed a prominent role for CCR2 in Ly6C+ pro-inflammatory monocyte/macrophage recruitment during metastasis progression, while inhibition of CCR2 signalling led to increased metastatic colony burden. CCR1 blockade, in contrast, suppressed late phase pro-tumour MR+Ly6C- monocyte/macrophage infiltration accompanied by expansion of the alveolar macrophage compartment and accumulation of NK cells, leading to reduced metastatic burden. These data indicate that IM has greater plasticity and higher phenotypic responsiveness to tumour challenge than AM. A considerable difference is also confirmed between CCR1 and CCR2 with regard to the recruited IM subsets, with CCR1 presenting a potential therapeutic target in pulmonary metastasis from melanoma. AU - Tapmeier, T.T.* AU - Howell, J.H.* AU - Zhao, L.* AU - Papiez, B.W.* AU - Schnabel, J.A. AU - Muschel, R.J.* AU - Gal, A.* C1 - 66490 C2 - 53192 SP - 5032–5045 TI - Evolving polarisation of infiltrating and alveolar macrophages in the lung during metastatic progression of melanoma suggests CCR1 as a therapeutic target. JO - Oncogene VL - 41 PY - 2022 SN - 0950-9232 ER - TY - JOUR AB - Oxidation of H3 at lysine 4 (H3K4ox) by lysyl oxidase-like 2 (LOXL2) generates an H3 modification with an unknown physiological function. We find that LOXL2 and H3K4ox are higher in triple-negative breast cancer (TNBC) cell lines and patient-derived xenografts (PDXs) than those from other breast cancer subtypes. ChIP-seq revealed that H3K4ox is located primarily in heterochromatin, where it is involved in chromatin compaction. Knocking down LOXL2 reduces H3K4ox levels and causes chromatin decompaction, resulting in a sustained activation of the DNA damage response (DDR) and increased susceptibility to anticancer agents. This critical role that LOXL2 and oxidized H3 play in chromatin compaction and DDR suggests that functionally targeting LOXL2 could be a way to sensitize TNBC cells to conventional therapy. AU - Cebrià-Costa, J.P.* AU - Pascual-Reguant, L.* AU - Gonzalez-Perez, A.* AU - Serra-Bardenys, G.* AU - Querol, J.* AU - Cosín, M.* AU - Verde, G.* AU - Cigliano, R.A.* AU - Sanseverino, W.* AU - Segura-Bayona, S.* AU - Iturbide Martinez De Albeniz, A. AU - Andreu, D.* AU - Nuciforo, P.* AU - Bernado-Morales, C.* AU - Rodilla, V.* AU - Arribas, J.* AU - Yelamos, J.* AU - de Herreros, A.G.* AU - Stracker, T.H.* AU - Peiró, S.* C1 - 57955 C2 - 48015 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England SP - 79-121 TI - LOXL2-mediated H3K4 oxidation reduces chromatin accessibility in triple-negative breast cancer cells. JO - Oncogene VL - 39 IS - 1 PB - Nature Publishing Group PY - 2020 SN - 0950-9232 ER - TY - JOUR AB - ZBTB7A is frequently mutated in acute myeloid leukemia (AML) with t(8;21) translocation. However, the oncogenic collaboration between mutated ZBTB7A and the RUNX1-RUNX1T1 fusion gene in AML t(8;21) remains unclear. Here, we investigate the role of ZBTB7A and its mutations in the context of normal and malignant hematopoiesis. We demonstrate that clinically relevant ZBTB7A mutations in AML t(8;21) lead to loss of function and result in perturbed myeloid differentiation with block of the granulocytic lineage in favor of monocytic commitment. In addition, loss of ZBTB7A increases glycolysis and hence sensitizes leukemic blasts to metabolic inhibition with 2-deoxy-d-glucose. We observed that ectopic expression of wild-type ZBTB7A prevents RUNX1-RUNX1T1-mediated clonal expansion of human CD34+ cells, whereas the outgrowth of progenitors is enabled by ZBTB7A mutation. Finally, ZBTB7A expression in t(8;21) cells lead to a cell cycle arrest that could be mimicked by inhibition of glycolysis. Our findings suggest that loss of ZBTB7A may facilitate the onset of AML t(8;21), and that RUNX1-RUNX1T1-rearranged leukemia might be treated with glycolytic inhibitors. AU - Redondo Monte, E.* AU - Wilding, A.* AU - Leubolt, G.* AU - Kerbs, P.* AU - Bagnoli, J.W.* AU - Hartmann, L.* AU - Hiddemann, W.* AU - Chen-Wichmann, L.* AU - Krebs, S.* AU - Blum, H.* AU - Cusan, M.* AU - Vick, B. AU - Jeremias, I. AU - Enard, W.* AU - Theurich, S.* AU - Wichmann, C.* AU - Greif, P.A.* C1 - 58606 C2 - 48213 CY - Macmillan Building, 4 Crinan St, London N1 9xw, England SP - 3195–3205 TI - ZBTB7A prevents RUNX1-RUNX1T1-dependent clonal expansion of human hematopoietic stem and progenitor cells. JO - Oncogene VL - 39 PB - Nature Publishing Group PY - 2020 SN - 0950-9232 ER - TY - JOUR AB - Taxane-based radiochemotherapy is a central treatment option for various cancer entities in locally advanced stages. The therapeutic synergism of this combined modality approach due to taxane-mediated radiosensitization of cancer cells is well-known. However, the underlying molecular mechanisms remain largely elusive, and mechanism-derived predictive markers of taxane-based radiochemotherapy are currently not available. Here, we show that clinically relevant doses of Paclitaxel, the prototype taxane, stimulate a tripolar mode of mitosis leading to chromosomal missegregation and aneuploidization rather than interfering with cell cycle progression. This distinct mitotic phenotype was interlinked with Paclitaxel-mediated radiosensitization via overexpression of mitotic Aurora kinase A (AURKA) and its cofactor TPX2 whose knockdown rescued the bipolar mode of cell division and largely attenuated the radiosensitizing effects of Paclitaxel. In the cancer genome atlas (TCGA) lung adenocarcinoma cohort, high expression levels of AURKA and TPX2 were associated with specifically improved overall survival upon taxane-based radiochemotherapy, but not in case of non-taxane-based radiochemotherapy, chemo- or radiotherapy only. Thus, our data provide insights into Paclitaxel-mediated radiosensitization on a mechanistic and molecular level and identify AURKA and TPX2 as the first potential mechanism-based, predictive markers of taxane-based radiochemotherapy. AU - Orth, M. AU - Unger, K. AU - Schoetz, U. AU - Belka, C. AU - Lauber, K. C1 - 52125 C2 - 43726 CY - London SP - 52-62 TI - Taxane-mediated radiosensitization derives from chromosomal missegregation on tripolar mitotic spindles orchestrated by AURKA and TPX2. JO - Oncogene VL - 37 IS - 1 PB - Nature Publishing Group PY - 2018 SN - 0950-9232 ER - TY - JOUR AB - The risk of several cancers, including colorectal cancer, is increased in patients with obesity and type 2 diabetes, conditions characterised by hyperinsulinaemia and insulin resistance. Because hyperinsulinaemia itself is an independent risk factor for cancer development, we examined tissue-specific insulin action in intestinal tumour formation. In vitro, insulin increased proliferation of intestinal tumour epithelial cells by almost two-fold in primary culture of tumour cells from Apc(Min/+) mice. Surprisingly, targeted deletion of insulin receptors in intestinal epithelial cells in Apc(Min/+) mice did not change intestinal tumour number or size distribution on either a low or high-fat diet. We therefore asked whether cells in the tumour stroma might explain the association between tumour formation and insulin resistance. To this end, we generated Apc(Min/+) mice with loss of insulin receptors in vascular endothelial cells. Strikingly, these mice had 42% more intestinal tumours than controls, no change in tumour angiogenesis, but increased expression of vascular cell adhesion molecule-1 (VCAM-1) in primary culture of tumour endothelial cells. Insulin decreased VCAM-1 expression and leukocyte adhesion in quiescent tumour endothelial cells with intact insulin receptors and partly prevented increases in VCAM-1 and leukocyte adhesion after treatment with tumour necrosis factor-a. Knockout of insulin receptors in endothelial cells also increased leukocyte adhesion in mesenteric venules and increased the frequency of neutrophils in tumours. We conclude that although insulin is mitogenic for intestinal tumour cells in vitro, impaired insulin action in the tumour microenvironment may be more important in conditions where hyperinsulinaemia is secondary to insulin resistance. Insulin resistance in tumour endothelial cells produces an activated, proinflammatory state that promotes tumorigenesis. Improvement of endothelial dysfunction may reduce colorectal cancer risk in patients with obesity and type 2 diabetes. AU - Wang, X.* AU - Haering, M.-F.* AU - Rathjen, T.* AU - Lockhart, S.M.* AU - Sorensen, D.* AU - Ussar, S. AU - Rasmussen, L.M.* AU - Bertagnolli, M.M.* AU - Kahn, C.R.* AU - Rask-Madsen, C.* C1 - 51867 C2 - 43538 CY - London SP - 4987-4996 TI - Insulin resistance in vascular endothelial cells promotes intestinal tumour formation. JO - Oncogene VL - 36 IS - 35 PB - Nature Publishing Group PY - 2017 SN - 0950-9232 ER - TY - JOUR AB - Human adenoviruses (HAdV) are used as a model system to investigate tumorigenic processes in mammalian cells where the viral oncoproteins E1A and E1B-55K are absolutely required for oncogenic transformation, because they simultaneously accelerate cell cycle progression and inhibit tumor suppressor proteins such as p53, although the underlying mechanism is still not understood in detail. In our present study, we provide evidence that E1B-55K binding to the PML-NB component Sp100A apparently has an essential role in regulating adenovirus-mediated transformation processes. Specifically, when this E1B-55K/Sp100A complex recruits p53, Sp100A-induced activation of p53 transcriptional activity is effectively abolished. Hence, Sp100A exhibits tumor-suppressive activity, not only by stabilizing p53 transactivation but also by depressing E1A/E1B-55K-mediated transformation. E1B-55K counteracts this suppressive activity, inducing Sp100A SUMOylation and sequestering the modified cellular factor into the insoluble matrix of the nucleus or into cytoplasmic inclusions. These observations provide novel insights into how E1B-55K modulates cellular determinants to maintain growth-promoting activity during oncogenic processes and lytic infection. AU - Berscheminski, J.* AU - Brun, J.* AU - Speiseder, T.* AU - Wimmer, P.* AU - Ip, W.H.* AU - Terzic, M. AU - Dobner, T.* AU - Schreiner, S. C1 - 47242 C2 - 39199 CY - London SP - 3178-3189 TI - Sp100A is a tumor suppressor that activates p53-dependent transcription and counteracts E1A/E1B-55K-mediated transformation. JO - Oncogene VL - 35 IS - 24 PB - Nature Publishing Group PY - 2016 SN - 0950-9232 ER - TY - JOUR AB - Constitutive activation of the antiapoptotic nuclear factor-κB (NF-κB) signaling pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL). Recurrent oncogenic mutations are found in the scaffold protein CARMA1 (CARD11) that connects B-cell receptor (BCR) signaling to the canonical NF-κB pathway. We asked how far additional downstream processes are activated and contribute to the oncogenic potential of DLBCL-derived CARMA1 mutants. To this end, we expressed oncogenic CARMA1 in the NF-κB negative DLBCL lymphoma cell line BJAB. By a proteomic approach we identified recruitment of β-catenin and its destruction complex consisting of APC, AXIN1, CK1α and GSK3β to oncogenic CARMA1. Recruitment of the β-catenin destruction complex was independent of CARMA1-BCL10-MALT1 complex formation or constitutive NF-κB activation and promoted the stabilization of β-catenin. The β-catenin destruction complex was also recruited to CARMA1 in ABC DLBCL cell lines, which coincided with elevated β-catenin expression. In line, β-catenin was frequently detected in non-GCB DLBCL biopsies that rely on chronic BCR signaling. Increased β-catenin amounts alone were not sufficient to induce classical WNT target gene signatures, but could augment TCF/LEF-dependent transcriptional activation in response to WNT signaling. In conjunction with NF-κB, β-catenin enhanced expression of immunosuppressive interleukin-10 and suppressed antitumoral CCL3, indicating that β-catenin can induce a favorable tumor microenvironment. Thus, parallel activation of NF-κB and β-catenin signaling by gain-of-function mutations in CARMA1 augments WNT stimulation and is required for regulating the expression of distinct NF-κB target genes to trigger cell-intrinsic and extrinsic processes that promote DLBCL lymphomagenesis. AU - Bognar, M. AU - Vincendeau, M. AU - Erdmann, T.* AU - Seeholzer, T. AU - Grau, M.* AU - Linnemann, J. AU - Ruland, J.* AU - Scheel, C. AU - Lenz, P.* AU - Ott, G.* AU - Lenz, G.* AU - Hauck, S.M. AU - Krappmann, D. C1 - 47705 C2 - 39554 CY - London SP - 4269-4281 TI - Oncogenic CARMA1 couples NF-κB and β-catenin signaling in diffuse large B-cell lymphomas. JO - Oncogene VL - 35 IS - 32 PB - Nature Publishing Group PY - 2016 SN - 0950-9232 ER - TY - JOUR AB - Activation of hypoxia-inducible factor (HIF) is due to loss of von Hippel-Lindau protein (pVHL) function in most clear cell renal cell carcinomas (ccRCCs). Here we describe a novel pVHL-independent mechanism of HIF regulation and identify nuclear factor (NF)-κB essential modulator (NEMO) as a hitherto unknown oncogenic factor influencing human ccRCC progression. Over 60% of human ccRCCs (n=157) have negative or weak NEMO protein expression by immunohistochemistry. Moderate/strong NEMO protein expression is more frequent in VHL wild-type ccRCCs. We show that NEMO stabilizes HIFα via direct interaction and independently of NF-κB signaling in vitro. NEMO prolongs tumor cell survival via regulation of apoptosis and activation of epithelial-to-mesenchymal transition, facilitating tumor metastasis. Our findings suggest that NEMO-driven HIF activation is involved in progression of ccRCC. Therefore, NEMO may represent a clinically relevant link between NF-κB and the VHL/HIF pathways. Targeting NEMO with specific inhibitors in patients with metastatic ccRCC could be a novel treatment approach in patients with ccRCC expressing functional pVHL. AU - Nowicka, A.M.* AU - Häuselmann, I.* AU - Borsig, L.* AU - Bolduan, S. AU - Schindler, M. AU - Schraml, P.* AU - Heikenwälder, M. AU - Moch, H.* C1 - 47236 C2 - 39306 CY - London SP - 3125-3138 TI - A novel pVHL-independent but NEMO-driven pathway in renal cancer promotes HIF stabilization. JO - Oncogene VL - 35 IS - 24 PB - Nature Publishing Group PY - 2016 SN - 0950-9232 ER - TY - JOUR AB - Although modulation of the cellular tumor-suppressor p53 is considered to have the major role in E1A/E1B-55K-mediated tumorigenesis, other promyelocytic leukemia nuclear body (PML-NB)/PML oncogenic domain (POD)-associated factors including SUMO, Mre11, Daxx, as well as the integrity of these nuclear bodies contribute to the transformation process. However, the biochemical consequences and oncogenic alterations of PML-associated E1B-55K by SUMO-dependent PML-IV and PML-V interaction have so far remained elusive. We performed mutational analysis to define a PML interaction motif within the E1B-55K polypeptide. Our results showed that E1B-55K/PML binding is not required for p53, Mre11 and Daxx interaction. We also observed that E1B-55K lacking subnuclear PML localization because of either PML-IV or PML-V-binding deficiency was no longer capable of mediating E1B-55K-dependent SUMOylation of p53, inhibition of p53-mediated transactivation or efficiently transforming primary rodent cells. These results together with the observation that E1B-55K-dependent SUMOylation of p53 is required for efficient cell transformation, provides evidence for the idea that the SUMO ligase activity of the E1B-55K viral oncoprotein is intimately linked to its growth-promoting oncogenic activities. AU - Wimmer, P.* AU - Berscheminski, J.* AU - Blanchette, P.* AU - Groitl, P.* AU - Branton, P.E.* AU - Hay, R.T.* AU - Dobner, T.* AU - Schreiner, S. C1 - 47278 C2 - 39196 SP - 69–82 TI - PML isoforms IV and V contribute to adenovirus-mediated oncogenic transformation by functionally inhibiting the tumor-suppressor p53. JO - Oncogene VL - 35 PY - 2016 SN - 0950-9232 ER - TY - JOUR AB - Lung cancer is the leading cause of cancer-related deaths worldwide. Recently, we have shown that Notch1 inhibition resulted in substantial cell death of non-small cell lung cancer (NSCLC) cells in vitro. New compounds targeting Notch signal transduction have been developed and are now being tested in clinical trials. However, the tumorigenic role of individual Notch receptors in vivo remains largely unclear. Using a Kras(G12D)-driven endogenous NSCLC mouse model, we analyzed the effect of conditional Notch1 and Notch2 receptor deletion on NSCLC tumorigenesis. Notch1 deficiency led to a reduced early tumor formation and lower activity of MAPK compared with the controls. Unexpectedly, Notch2 deletion resulted in a dramatically increased carcinogenesis and increased MAPK activity. These mice died significantly earlier due to rapidly growing tumor burden. We found that Notch1 regulates Ras/MAPK pathway via HES1-induced repression of the DUSP1 promoter encoding a phosphatase specifically suppressing pERK1/2. Interestingly, Notch1 but not Notch2 ablation leads to decreased HES1 and DUSP1 expression. However, Notch2-depleted tumors showed an appreciable increase in β-catenin expression, a known activator of HES1 and important lung cancer oncogene. Characteristically for β-catenin upregulation, we found that the majority of Notch2-deficient tumors revealed an undifferentiated phenotype as determined by their morphology, E-Cadherin and TTF1 expression levels. In addition, these carcinomas showed aggressive growth patterns with bronchus invasion and obstruction. Together, we show that Notch2 mediates differentiation and has tumor suppressor functions during lung carcinogenesis, whereas Notch1 promotes tumor initiation and progression. These data are further supported by immunohistochemical analysis of human NSCLC samples showing loss or downregulation of Notch2 compared with normal lung tissue. In conclusion, this is the first study characterizing the in vivo functions of Notch1 and Notch2 in Kras(G12D)-driven NSCLC tumorigenesis. These data highlight the clinical importance of a thorough understanding of Notch signaling especially with regard to Notch-targeted therapies. AU - Baumgart, A.* AU - Mazur, P.K.* AU - Anton, M.* AU - Rudelius, M.* AU - Schwamborn, K.* AU - Feuchtinger, A. AU - Behnke, K.* AU - Walch, A.K. AU - Braren, R.* AU - Peschel, C.* AU - Duyster, J.* AU - Siveke, J.T.* AU - Dechow, T.* C1 - 29319 C2 - 33690 CY - London SP - 578–588 TI - Opposing role of Notch1 and Notch2 in a KrasG12D-driven murine non-small cell lung cancer model. JO - Oncogene VL - 34 IS - 5 PB - Nature Publishing Group PY - 2015 SN - 0950-9232 ER - TY - JOUR AB - PINK1 (phosphatase and tensin homolog deleted on chromosome 10 (PTEN)-induced kinase 1), a Parkinson's disease-associated gene, was identified originally because of its induction by the tumor-suppressor PTEN. PINK1 promotes cell survival and potentially metastatic functions and protects against cell stressors including chemotherapeutic agents. However, the mechanisms underlying PINK1 function in cancer cell biology are unclear. Here, using several model systems, we show that PINK1 deletion significantly reduced cancer-associated phenotypes including cell proliferation, colony formation and invasiveness, which were restored by human PINK1 overexpression. Results show that PINK1 deletion causes major defects in cell cycle progression in immortalized mouse embryonic fibroblasts (MEFs) from PINK1(-/-) mice, and in BE(2)-M17 cells stably transduced with short hairpin RNA against PINK1. Detailed cell cycle analyses of MEF cell lines from several PINK1(-/-) mice demonstrate an increased proportion of cells in G2/M and decreased number of cells in G1 following release from nocodazole block. This was concomitant with increased double and multi-nucleated cells, a reduced ability to undergo cytokinesis and to re-enter G1, and significant alterations in cell cycle markers, including failure to increase cyclin D1, all indicative of mitotic arrest. PINK1(-/-) cells also demonstrated ineffective cell cycle exit following serum deprivation. Cell cycle defects associated with PINK1 deficiency occur at points critical for cell division, growth and stress resistance in cancer cells were rescued by ectopic expression of human PINK1 and demonstrated PINK1 kinase dependence. The importance of PINK1 for cell cycle control is further supported by results showing that cell cycle deficits induced by PINK1 deletion were linked mechanistically to aberrant mitochondrial fission and its regulation by dynamin-related protein-1 (Drp1), known to be critical for progression of mitosis. Our data indicate that PINK1 has tumor-promoting properties and demonstrates a new function for PINK1 as a regulator of the cell cycle. AU - O'Flanagan, C.H.* AU - Morais, V.A.* AU - Wurst, W. AU - de Strooper, B.* AU - O'Neill, C.* C1 - 30942 C2 - 34040 CY - London SP - 1363-1374 TI - The Parkinson's gene PINK1 regulates cell cycle progression and promotes cancer-associated phenotypes. JO - Oncogene VL - 34 IS - 11 PB - Nature Publishing Group PY - 2015 SN - 0950-9232 ER - TY - JOUR AB - A substantial increase in papillary thyroid carcinoma (PTC) among children exposed to the radioiodine fallout has been one of the main consequences of the Chernobyl reactor accident. Recently, the investigation of PTCs from a cohort of young patients exposed to the post-Chernobyl radioiodine fallout at very young age and a matched nonexposed control group revealed a radiation-specific DNA copy number gain on chromosomal band 7q11.23 and the radiation-associated mRNA overexpression of CLIP2. In this study, we investigated the potential role of CLIP2 as a radiation marker to be used for the individual classification of PTCs into CLIP2-positive and -negative cases-a prerequisite for the integration of CLIP2 into epidemiological modelling of the risk of radiation-induced PTC. We were able to validate the radiation-associated CLIP2 overexpression at the protein level by immunohistochemistry (IHC) followed by relative quantification using digital image analysis software (P=0.0149). Furthermore, we developed a standardized workflow for the determination of CLIP2-positive and -negative cases that combines visual CLIP2 IHC scoring and CLIP2 genomic copy number status. In addition to the discovery cohort (n=33), two independent validation cohorts of PTCs (n=115) were investigated. High sensitivity and specificity rates for all three investigated cohorts were obtained, demonstrating robustness of the developed workflow. To analyse the function of CLIP2 in radiation-associated PTC, the CLIP2 gene regulatory network was reconstructed using global mRNA expression data from PTC patient samples. The genes comprising the first neighbourhood of CLIP2 (BAG2, CHST3, KIF3C, NEURL1, PPIL3 and RGS4) suggest the involvement of CLIP2 in the fundamental carcinogenic processes including apoptosis, mitogen-activated protein kinase signalling and genomic instability. In our study, we successfully developed and independently validated a workflow for the typing of PTC clinical samples into CLIP2-positive and CLIP2-negative and provided first insights into the CLIP2 interactome in the context of radiation-associated PTC. AU - Selmansberger, M.* AU - Feuchtinger, A. AU - Zurnadzhy, L.* AU - Michna, A. AU - Kaiser, J.C. AU - Abend, M.* AU - Brenner, A.* AU - Bogdanova, T.* AU - Walch, A.K. AU - Unger, K. AU - Zitzelsberger, H. AU - Hess J. C1 - 32452 C2 - 35032 CY - London SP - 3917-3925 TI - CLIP2 as radiation biomarker in papillary thyroid carcinoma. JO - Oncogene VL - 34 IS - 30 PB - Nature Publishing Group PY - 2015 SN - 0950-9232 ER - TY - JOUR AB - The discovery of constitutive nuclear factor-κB (NF-κB) activation in Hodgkin's lymphoma tumor cells almost two decades ago was one of the first reports that directly connected deregulated NF-κB signaling to human cancer. Subsequent studies demonstrated that enhanced NF-κB signaling is a common hallmark of many lymphoid malignancies, including Hodgkin lymphoma, mucosa-associated lymphoid tissue lymphoma, diffuse large B-cell lymphoma and multiple myeloma. By inducing an anti-apoptotic and pro-proliferative gene program, NF-κB is involved in lymphoma survival and growth. Identification of somatic mutations that led to activation of oncogenes and inactivation of tumor suppressor genes in the pathway revealed that specific pathogenic mechanisms are responsible for constitutive NF-κB activation in different lymphoma entities. Thus, the identification of distinct oncogenic events is reflecting the diverse cellular origins of the different lymphomas. Further, elucidation of the mechanisms that drive NF-κB in lymphoma is of high clinical relevance as it will allow the design of target-directed precision therapy. Indeed, a number of drugs that impair constitutive NF-κB activation in lymphoid malignancies are currently in preclinical or clinical development. AU - Nagel, D. AU - Vincendeau, M. AU - Eitelhuber, A.C. AU - Krappmann, D. C1 - 30746 C2 - 33830 SP - 5655-5665 TI - Mechanisms and consequences of constitutive NF-κB activation in B-cell lymphoid malignancies. JO - Oncogene VL - 33 IS - 50 PY - 2014 SN - 0950-9232 ER - TY - JOUR AB - Epstein-Barr virus (EBV) has evolved exquisite controls over its host cells, human B lymphocytes, not only directing these cells during latency to proliferate and thereby expand the pool of infected cells, but also to survive and thereby persist for the lifetime of the infected individual. Although these activities ensure the virus is successful, they also make the virus oncogenic, particularly when infected people are immunosuppressed. Here we show, strikingly, that one set of EBV's microRNAs (miRNAs) both sustain Burkitt's lymphoma (BL) cells in the absence of other viral oncogenes and promote the transformation of primary B lymphocytes. BL cells were engineered to lose EBV and found to die by apoptosis and could be rescued by constitutively expressing viral miRNAs in them. Two of these EBV miRNAs were found to target caspase 3 to inhibit apoptosis at physiological concentrations. AU - Vereide, D.T.* AU - Seto, E. AU - Chiu, Y.F.* AU - Hayes, M.* AU - Tagawa, T. AU - Grundhoff, A.* AU - Hammerschmidt, W. AU - Sugden, B.* C1 - 26294 C2 - 32156 CY - London SP - 1258-1264 TI - Epstein-Barr virus maintains lymphomas via its miRNAs. JO - Oncogene VL - 44 IS - 10 PB - Nature Publishing PY - 2014 SN - 0950-9232 ER - TY - JOUR AB - The tumor microenvironment consists of stromal cells and leukocytes that contribute to cancer progression. Cross-talk between tumor cells and their microenvironment is facilitated by a variety of soluble factors, including growth factors and cytokines such as chemokines. Due to a wide expression of chemokine receptors on cells in the tumor microenvironment, including tumor cells, chemokines affect various processes such as leukocyte recruitment, angiogenesis, tumor cell survival, tumor cell adhesion, proliferation, vascular permeability, immune suppression, invasion and metastasis. Inflammatory chemokines are instrumental players in cancer-related inflammation and significantly contribute to numerous steps during metastasis. Recruitment of myeloid-derived cells to metastatic sites is mainly mediated by the inflammatory chemokines CCL2 and CCL5. Tumor cell homing and extravasation from the circulation to distant organs are also regulated by inflammatory chemokines. Recent experimental evidence demonstrated that besides leukocyte recruitment, tumor cell-derived CCL2 directly activated endothelial cells and together with monocytes facilitated tumor cell extravasation, in a CCL2- and CCL5-dependent manner. Furthermore, CX3CL1 expression in the bone facilitated metastasis of CX3CR1 expressing tumor cells to this site. Current findings in preclinical models strongly suggest that inflammatory chemokines have an important role during metastasis and targeting of the chemokine axis might have a therapeutic potential. AU - Borsig, L.* AU - Wolf, M.J.* AU - Roblek, M.* AU - Lorentzen, A.R. AU - Heikenwälder, M. C1 - 28295 C2 - 33087 CY - London SP - 3217-3224 TI - Inflammatory chemokines and metastasis - tracing the accessory. JO - Oncogene VL - 33 IS - 25 PB - Nature Publishing PY - 2013 SN - 0950-9232 ER - TY - JOUR AB - The epithelial cell adhesion molecule (EpCAM) is an integral transmembrane protein that is frequently overexpressed in embryonic stem cells, tissue progenitors, carcinomas and cancer-initiating cells. In cancer cells, expression of EpCAM is associated with enhanced proliferation and upregulation of target genes including c-myc. However, the exact molecular mechanisms underlying the observed EpCAM-dependent cell proliferation remained unexplored. Here, we show that EpCAM directly affects cell cycle progression via its capacity to regulate the expression of cyclin D1 at the transcriptional level and depending on the direct interaction partner FHL2 (four-and-a-half LIM domains protein 2). As a result, downstream events such as phosphorylation of the retinoblastoma protein (Rb) and expression of cyclins E and A are similarly affected. In vivo, EpCAM expression strength and pattern are both positively correlated with the proliferation marker Ki67, high expression and nuclear localisation of cyclin D1, and Rb phosphorylation. Thus, EpCAM enhances cell cycle progression via the classical cyclin-regulated pathway. AU - Chaves-Perez, A. AU - Mack, B.* AU - Maetzel, D.* AU - Kremling, H. AU - Eggert, C. AU - Harréus, U.* AU - Gires, O. C1 - 23757 C2 - 31280 SP - 641-650 TI - EpCAM regulates cell cycle progression via control of cyclin D1 expression. JO - Oncogene VL - 32 IS - 5 PB - Nature Publishing PY - 2013 SN - 0950-9232 ER - TY - JOUR AB - AVEN has been identified as an inhibitor of apoptosis, which binds to the adaptor protein, APAF-1, and thereby prevents apoptosome formation and mitochondrial apoptosis. Recent data have demonstrated high expression levels of AVEN messenger RNA in acute leukemias as well as a positive correlation between AVEN mRNA overexpression and poor prognosis in childhood acute lymphoblastic leukemia. On the basis of these data, we investigated the potential involvement of AVEN in tumorigenesis. First, we confirmed the overexpression of AVEN in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) patient samples. We then established a transgenic mouse model with T-cell-specific overexpression of AVEN, with which we demonstrated the oncogenic cooperation of AVEN with heterozygous loss of p53. Finally, we used a subcutaneous xenograft mouse model to show that AVEN knockdown in the T-ALL cell lines, MOLT-4 and CCRF-CEM, and in the acute myeloblastic leukemia cell line, Kasumi-1, leads to a halt in tumor growth owing to the increased apoptosis and decreased proliferation of tumor cells. Collectively, our data demonstrate that the anti-apoptotic molecule, AVEN, functions as an oncoprotein in hematopoietic neoplasms. AU - Eißmann, M.* AU - Melzer, I.M.* AU - Fernández, S.B.* AU - Michel, G. AU - Hrabě de Angelis, M. AU - Hoefler, G.* AU - Finkenwirth, P.* AU - Jauch, A.* AU - Schoell, B.* AU - Grez, M.* AU - Schmidt, M.* AU - Bartholomae, C.C.* AU - Newrzela, S.* AU - Haetscher, N.* AU - Rieger, M.* AU - Zachskorn, C.* AU - Mittelbronn, M.* AU - Zörnig, M.* C1 - 8333 C2 - 30063 SP - 2586–2591 TI - Overexpression of the anti-apoptotic protein AVEN contributes to increased malignancy in hematopoietic neoplasms. JO - Oncogene VL - 32 IS - 20 PB - Nature Publishing PY - 2013 SN - 0950-9232 ER - TY - JOUR AB - Inappropriate activation of the NOTCH signaling pathway, for example, by activating mutations, contributes to the pathogenesis of various human malignancies. Here, we demonstrate that aberrant expression of an essential NOTCH coactivator of the Mastermind-like (MAML) family provides an alternative mechanism to activate NOTCH signaling in human lymphoma cells. We detected high-level MAML2 expression in several B cell-derived lymphoma types, including classical Hodgkin lymphoma (cHL) cells, relative to normal B cells. Inhibition of MAML-protein activity by a dominant negative form of MAML or by small hairpin RNAs targeting MAML2 in cHL cells resulted in downregulation of the NOTCH target genes HES7 and HEY1, which we identified as overexpressed in cHL cells, and in reduced proliferation. Furthermore, a NOTCH gene-expression signature in cHL cells confirmed their cell-autonomous NOTCH activity. Finally, in line with the essential role of MAML proteins for assembly and activity of the NOTCH transcriptional complex (NTC), we show that MAML-derived small-peptide constructs block NOTCH activity and disrupt NTC formation in vitro. These data strongly suggest direct targeting of the NTC as treatment strategy for NOTCH-dependent malignancies. AU - Köchert, K.* AU - Ullrich, K.* AU - Kreher, S.* AU - Aster, J.C.* AU - Kitagawa, M.* AU - Jöhrens, K.* AU - Anagnostopoulos, I.* AU - Jundt, F.* AU - Lamprecht, B.* AU - Zimber-Strobl, U. AU - Stein, H.* AU - Janz, M.* AU - Dörken, B.* AU - Mathas, S.* C1 - 6486 C2 - 28763 CY - Basingstoke, UK SP - 1831-1840 TI - High-level expression of Mastermind-like 2 contributes to aberrant activation of the NOTCH signaling pathway in human lymphomas. JO - Oncogene VL - 30 IS - 15 PB - Nature Publ. Group PY - 2011 SN - 0950-9232 ER - TY - JOUR AB - Heterozygous Patched1 (Ptc1(+/-)) mice are prone to medulloblastoma (MB), and exposure of newborn mice to ionizing radiation dramatically increases the frequency and shortens the latency of MB. In Ptc1(+/-) mice, MB is characterized by loss of the normal remaining Ptc1 allele, suggesting that genome rearrangements may be key events in MB development. Recent evidence indicates that brain tumors may be linked to defects in DNA-damage repair processes, as various combinations of targeted deletions in genes controlling cell-cycle checkpoints, apoptosis and DNA repair result in MB in mice. Non-homologous end joining (NHEJ) and homologous recombination (HR) contribute to genome stability, and deficiencies in either pathway predispose to genome rearrangements. To test the role of defective HR or NHEJ in tumorigenesis, control and irradiated Ptc1(+/-) mice with two, one or no functional Rad54 or DNA-protein kinase catalytic subunit (DNA-PKcs) alleles were monitored for MB development. We also examined the effect of Rad54 or DNA-PKcs deletion on the processing of endogenous and radiation-induced double-strand breaks (DSBs) in neural precursors of the developing cerebellum, the cells of origin of MB. We found that, although HR and NHEJ collaborate in protecting cells from DNA damage and apoptosis, they have opposite roles in MB tumorigenesis. In fact, although Rad54 deficiency increased both spontaneous and radiation-induced MB development, DNA-PKcs disruption suppressed MB tumorigenesis. Together, our data provide the first evidence that Rad54-mediated HR in vivo is important for suppressing tumorigenesis by maintaining genomic stability.Oncogene advance online publication, 23 May 2011; doi:10.1038/onc.2011.178. AU - Tanori, M.* AU - Pasquali, E.* AU - Leonardi, S.* AU - Giardullo, P.* AU - di Majo, V.* AU - Taccioli, G.* AU - Essers, J.* AU - Kanaar, R.* AU - Mullenders, L.H.* AU - Atkinson, M.J. AU - Mancuso, M.* AU - Saran, A.* AU - Pazzaglia, S.* C1 - 6254 C2 - 29065 SP - 4740-4749 TI - Opposite modifying effects of HR and NHEJ deficiency on cancer risk in Ptc1 heterozygous mouse cerebellum. JO - Oncogene VL - 30 IS - 47 PB - Nature Publ. Group PY - 2011 SN - 0950-9232 ER - TY - JOUR AB - The germinal center (GC) reaction has a pivotal function in human B-cell lymphomagenesis. Genetic aberrations occurring during somatic hypermutation and class switch recombination deregulate key factors controlling B-cell physiology and proliferation. Several human lymphoma entities are characterized by a constitutive GC phenotype and ongoing somatic hypermutation, but the molecular basis for this phenomenon is only partly understood. We have investigated the reasons for a constitutive GC-like program in Burkitt's lymphoma cells. Here, overexpression of c-Myc leads to a centroblast phenotype, promotes high constitutive expression of the key GC factors Bcl-6, E2A and activation-induced cytidine deaminase and contributes to proliferation and somatic hypermutation. Our findings elucidate how the activity of a pivotal transcription factor may freeze B-cell lymphoma cells in a constitutive GC-like state that is even maintained at an extrafollicular location. AU - Scheller, H. AU - Tobollik, S. AU - Kutzera, A. AU - Eder, M. AU - Unterlehberg, J. AU - Pfeil, I. AU - Jungnickel, B. C1 - 93 C2 - 26103 SP - 888-897 TI - c-Myc overexpression promotes a germinal center-like program in Burkitt's lymphoma. JO - Oncogene VL - 29 IS - 6 PY - 2010 SN - 0950-9232 ER - TY - JOUR AB - The cytokines lymphotoxin (LT) alpha, beta and their receptor (LTbetaR) belong to the tumor necrosis factor (TNF) superfamily, whose founder-TNFalpha-was initially discovered due to its tumor necrotizing activity. LTbetaR signaling serves pleiotropic functions including the control of lymphoid organ development, support of efficient immune responses against pathogens due to maintenance of intact lymphoid structures, induction of tertiary lymphoid organs, liver regeneration or control of lipid homeostasis. Signaling through LTbetaR comprises the noncanonical/canonical nuclear factor-kappaB (NF-kappaB) pathways thus inducing chemokine, cytokine or adhesion molecule expression, cell proliferation and cell survival. Blocking LTbetaR signaling or Fcgamma-receptor mediated immunoablation of LT-expressing cells was demonstrated to be beneficial in various infectious or noninfectious inflammatory or autoimmune disorders. Only recently, LTbetaR signaling was shown to initiate inflammation-induced carcinogenesis, to influence primary tumorigenesis and to control reemergence of carcinoma in various cancer models through distinct mechanisms. Indeed, LTbetaR signaling inhibition has already been used as efficient anti-inflammatory, anti-cancer therapy in some experimental models. Here, we review the pleiotropic functions attributed to LT, the effects of its deregulation and extensively discuss the recent literature on LT's link to carcinogenesis. AU - Wolf, M.J.* AU - Seleznik, G.M.* AU - Zeller, N.* AU - Heikenwälder, M. C1 - 292 C2 - 27705 SP - 5006-5018 TI - The unexpected role of lymphotoxin β receptor signaling in carcinogenesis: From lymphoid tissue formation to liver and prostate cancer development. JO - Oncogene VL - 29 IS - 36 PB - Nature Publ. Group PY - 2010 SN - 0950-9232 ER - TY - JOUR AB - The glutathione-dependent system is one of the key systems regulating cellular redox balance, and thus cell fate. Cysteine, typically present in its oxidized form cystine in the extracellular space, is regarded as the rate-limiting substrate for glutathione (GSH) synthesis. Cystine is transported into cells by the highly specific amino-acid antiporter system xc-. Since Burkitt's Lymphoma (BL) cells display limited uptake capacity for cystine, and are thus prone to oxidative stress-induced cell death, we stably expressed the substrate-specific subunit of system xc-, xCT, in HH514 BL cells. xCT-overexpressing cells became highly resistant to oxidative stress, particularly upon GSH depletion. Contrary to previous predictions, the increase of intracellular cysteine did not affect the cellular GSH pool, but concomitantly boosted extracellular cysteine concentrations. Even though cells were depleted of bulk GSH, xCT overexpression maintained cellular integrity by protecting against lipid peroxidation, a very early event in cell death progression. Our results show that system xc- protects against oxidative stress not by elevating intracellular GSH levels, but rather creates a reducing extracellular environment by driving a highly efficient cystine/cysteine redox cycle. Our findings show that the cystine/cysteine redox cycle by itself must be viewed as a discrete major regulator of cell survival. AU - Banjac, A. AU - Perisic, T. AU - Sato, H.* AU - Seiler, A. AU - Bannai, S.* AU - Weiss, N.* AU - Kölle, P.* AU - Tschoep, K.* AU - Issels, R.D.* AU - Daniel, PT.* AU - Conrad, M. AU - Bornkamm, G.W. C1 - 2346 C2 - 25332 SP - 1618-1628 TI - The cystine/cysteine cycle: A redox cycle regulating susceptibility versus resistance to cell death. JO - Oncogene VL - 27 IS - 11 PB - Nature Publ. Group PY - 2008 SN - 0950-9232 ER - TY - JOUR AB - Apoptosis resistance is crucially involved in cancer development and progression, represents the leading cause for failure of anticancer therapy and is caused, for example, by downregulation of proapoptotic intracellular signaling molecules such as caspase-8. We found that the cytotoxic drugs methotrexate (MTX) and 5-fluorouracil (5-FU) were both able to sensitize resistant tumor cells for induction of apoptosis by p53-mediated upregulation of caspase-8. Increase in caspase-8 messenger RNA and protein expression disabled tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced proliferation and restored sensitivity toward TRAIL-induced apoptosis which was inhibited by transfection of p53 decoy oligonucleotides, p53 shRNA and caspase-8 shRNA. Upregulation of caspase-8 and sensitization toward TRAIL-induced apoptosis was found both in a broad panel of tumor cell lines with downregulated caspase-8 and in TRAIL-resistant primary tumor cells of children with acute leukemia. Taken together, we have identified caspase-8 as an important p53 target gene regulated by cytotoxic drugs. These findings highlight a new drug-induced modulation of physiological apoptosis pathways, which may be involved in successful anticancer therapy using MTX and 5-FU in leukemia and solid tumors over decades. AU - Ehrhardt, H.* AU - Häcker, S.* AU - Wittmann, S.* AU - Maurer, M.* AU - Borkhardt, A.* AU - Toloczko, A. AU - Debatin, K.M.* AU - Fulda, S.* AU - Jeremias, I. C1 - 2333 C2 - 25538 SP - 783-793 TI - Cytotoxic drug-induced, p53-mediated upregulation of caspase-8 in tumor cells. JO - Oncogene VL - 27 IS - 6 PB - Nature Publ. Group PY - 2008 SN - 0950-9232 ER - TY - JOUR AB - Tumors that acquire resistance against death stimuli constitute a severe problem in the context of cancer therapy. To determine genetic alterations that favor the development of stress-resistant tumors in vivo, we took advantage of polyclonal tumors generated after retroviral infection of newborn Elambda-MYC mice, in which the retroviral integration acts as a mutagen to enhance tumor progression. Tumor cells were cultivated ex vivo and exposed to gamma-irradiation prior to their transplantation into syngenic recipients, thereby providing a strong selective pressure for pro-survival mutations. Secondary tumors developing from stress-resistant tumor stem cells were analysed for retroviral integration sites to reveal candidate genes whose dysregulation confer survival. In addition to the gene encoding the antiapoptotic Bcl-x(L) protein, we identified the gadd45b locus to be a novel common integration site in these tumors, leading to enhanced expression. In accord with a thus far undocumented role of Gadd45beta in tumorigenesis, we showed that NIH3T3 cells overexpressing Gadd45beta form tumors in NOD/SCID mice. Interestingly and differently to other known 'classical' antiapoptotic factors, high Gadd45beta levels did not protect against MYC-, UV- or gamma-irradiation-induced apoptosis, but conferred a strong and specific survival advantage to serum withdrawal. AU - Engelmann, A.* AU - Speidel, D.* AU - Bornkamm, G.W. AU - Deppert, W.* AU - Stocking, C.* C1 - 6213 C2 - 28388 SP - 1429-1438 TI - Gadd45β is a pro-survival factor associated with stress-resistant tumors. JO - Oncogene VL - 27 IS - 10 PB - Nature Publ. Group PY - 2008 SN - 0950-9232 ER - TY - JOUR AB - The t(10;11)(p13;q14) translocation leads to the fusion of the CALM and AF10 genes. This translocation can be found as the sole cytogenetic abnormality in acute lymphoblastic leukemia, acute myeloid leukemia and in malignant lymphomas. The expression of CALM/AF10 in primary murine bone marrow cells results in the development of an aggressive leukemia in a murine bone marrow transplantation model. Using a yeast two-hybrid screen, we identified the lymphoid regulator Ikaros as an AF10 interacting protein. Interestingly, Ikaros is required for normal development of lymphocytes, and aberrant expression of Ikaros has been found in leukemia. In a murine model, the expression of a dominant negative isoform of Ikaros causes leukemias and lymphomas. The Ikaros interaction domain of AF10 was mapped to the leucine zipper domain of AF10, which is required for malignant transformation both by the CALM/AF10 and the MLL/AF10 fusion proteins. The interaction between AF10 and Ikaros was confirmed by GST pull down and co-immunoprecipitation. Coexpression of CALM/AF10 but not of AF10 alters the subcellular localization of Ikaros in murine fibroblasts. The transcriptional repressor activity of Ikaros is reduced by AF10. These results suggest that CALM/AF10 might interfere with normal Ikaros function, and thereby block lymphoid differentiation in CALM/AF10 positive leukemias. AU - Greif, P.A. AU - Tizazu, B.* AU - Krause, A.J. AU - Kremmer, E. AU - Bohlander, S.K. C1 - 3321 C2 - 25688 SP - 2886-2896 TI - The leukemogenic CALM/AF10 fusion protein alters the subcellular localization of the lymphoid regulator Ikaros. JO - Oncogene VL - 27 IS - 20 PB - Nature Publ. Group PY - 2008 SN - 0950-9232 ER - TY - JOUR AB - Inhibition of p53-activated transcription is an integral part of the mechanism by which early region 1B 55K oncoprotein (E1B-55K) from adenovirus type 5 (Ad5) contributes to complete cell transformation in combination with Ad E1A. In addition, more recent data suggest that the mode of action of the Ad protein during transformation may involve additional functions and other protein interactions. In the present study, we performed a comprehensive mutational analysis to assign further transforming functions of Ad5 E1B-55K to distinct domains within the viral polypeptide. Results from these studies show that the functions required for transformation are encoded within several patches of the 55K primary sequence, including several clustered cysteine and histidine residues, some of which match the consensus for zinc fingers. In addition, two amino-acid substitutions (C454S/C456S) created a 55K mutant protein, which had substantially reduced transforming activity. Interestingly, the same mutations neither affected binding to p53 nor inhibition of p53-mediated transactivation. Therefore, an activity necessary for efficient transformation of primary rat cells can be separated from functions required for inhibition of p53-stimulated transcription. Our data indicate that this activity is linked to the ability of the Ad5 protein to bind to components of the Mre11/Rad50/NBS1 DNA double-strand break repair complex, and/or its ability to assemble multiprotein aggregates in the cytoplasm and nucleus of transformed rat cells. These results introduce a new function for Ad5 E1B-55K and suggest that the viral protein contributes to cell transformation through p53 transcription-dependent and -independent pathways. AU - Härtl, B.* AU - Zeller, T.* AU - Blanchette, P.* AU - Kremmer, E. AU - Dobner, T.* C1 - 2430 C2 - 25692 SP - 3673-3684 TI - Adenovirus type 5 early region 1B 55-kDa oncoprotein can promote cell transformation by a mechanism independent from blocking p53-activated transcription. JO - Oncogene VL - 27 IS - 26 PB - Nature Publ. Group PY - 2008 SN - 0950-9232 ER - TY - JOUR AB - The aim of this study is to investigate additional genetic alterations in papillary thyroid carcinomas (PTCs) with known RET/PTC rearrangements. We applied array-based comparative genomic hybridization (array CGH) to 33 PTC (20 PTC from adults, 13 post-Chernobyl PTC from children) with known RET/PTC status. Principal component analysis and hierarchical cluster analysis identified cases with similar aberration patterns. Significant deviations between tumour-groups were obtained by statistical testing (Fisher's exact test in combination with Benjamini-Hochberg FDR-controlling procedure). FISH analysis on FFPE sections was applied to validate the array CGH data. Deletions were found more frequently in RET/PTC-positive and RET/PTC-negative tumours than amplifications. Specific aberration signatures were identified that discriminated between RET/PTC-positive and RET/PTC-negative cases (aberrations on chromosomes 1p, 3q, 4p, 7p, 9p/q, 10q, 12q, 13q and 21q). In addition, childhood and adult RET/PTC-positive cases differ significantly for a deletion on the distal part of chromosome 1p. There are additional alterations in RET/PTC-positive tumours, which may act as modifiers of RET activation. In contrast, alterations in RET/PTC-negative tumours indicate alternative routes of tumour development. The data presented serve as a starting point for further studies on gene expression and function of genes identified in this study. AU - Unger, K. AU - Malisch, E. AU - Thomas, G.* AU - Braselmann, H. AU - Walch, A.K. AU - Jackl, G. AU - Lewis, P.* AU - Lengfelder, E.* AU - Bogdanova, T.* AU - Wienberg, J.* AU - Zitzelsberger, H. C1 - 4902 C2 - 25407 SP - 4592-4602 TI - Array CGH demonstrates characteristic aberration signatures in human papillary thyroid carcinomas governed by RET/PTC. JO - Oncogene VL - 27 IS - 33 PB - Nature Publ. Group PY - 2008 SN - 0950-9232 ER - TY - JOUR AB - An acidic domain (AD) of gp130 was previously found to interact with the Src family kinase (SFK) Hck. Here, the influence of myristoylated peptides derived from this AD was assessed in the mouse myeloma cell line, 7TD1. The IL-6-dependent growth of 7TD1 cells was reduced by approximately 75%, if 100 microM of myristoylated 18mer peptide (18AD) was included in the growth medium, but was unaffected by a control peptide with scrambled sequence (18sc). A similar differential inhibition by peptides 18AD and 18sc was observed for the erythropoietin-dependent growth of BaF-EH cells expressing chimeric erythropoietin receptor-gp130 and human Hck and for the human myeloma cell line INA-6. While the peptide 18AD concentration inhibiting 50% was approximately 30 microM in 7TD1 and BaF-EH cells, peptide 18AD did not significantly inhibit growth of IL-6-independent MM1.S myeloma and OKT1 hybridoma cells or of BaF-EH cells supplied with IL-3. Treatment with 100 microM peptide 18AD caused the same degree or 60% of apoptosis induction as IL-6 deprivation in 7TD1 or INA-6 cells, respectively. Co-immunoprecipitation experiments revealed that peptide 18AD interfered with the association of Hck and gp130 in 7TD1 lysates in a concentration-dependent manner. IL-6-treatment of INA-6 cells induced the kinase activities of Fyn, Lyn and Hck, but not Src, and the IL-6-induced SFK activities were inhibited by peptide 18AD. Expression in 7TD1 cells of a kinase-inactive Hck mutant (K269R) elicited a dominant-negative effect on cell number increases providing further evidence that SFKs are required for gp130 signalling in myeloma cells. AU - Hausherr, A. AU - Tavares, R. AU - Schäffer, M.* AU - Obermeier, A.* AU - Miksch, C.* AU - Mitina, O. AU - Ellwart, J.W. AU - Hallek, M. AU - Krause, G. C1 - 4904 C2 - 24711 SP - 4987-4998 TI - Inhibition of IL-6-dependent growth of myeloma cells by an acidic peptide repressing the gp130-mediated activation of Src family kinases. JO - Oncogene VL - 26 IS - 34 PB - Nature Publ. Group PY - 2007 SN - 0950-9232 ER - TY - JOUR AB - The human herpes virus 8 (HHV-8)-encoded G protein-coupled chemokine receptor (vGPCR) has been implicated in the pathogenesis of Kaposi's sarcoma (KS), particularly because of its high constitutive signaling activity. Here, we used retroviral transduction to generate vGPCR-expressing 3T3 fibroblasts that are tumorigenic in nude mice, but as expected fail to induce tumors in their immunocompetent counterparts. However, tumor fragments obtained from nude mice grow progressively in immunocompetent BALB/c mice. Unexpectedly, vGPCR-expressing cells established from grafted tumor fragments gave rise to tumors in immunocompetent mice. These tumors exhibit a striking histological resemblance to KS including plump spindle cell morphology, a high degree of vascularization and brisk mitotic activity. High expression of vGPCR was confirmed in the cell lines and tumors using a newly developed vGPCR-specific monoclonal antibody. Finally, short interfering RNA directed at vGPCR abrogated or significantly delayed tumorigenesis in mice, demonstrating that the tumor development is specifically driven by vGPCR. This novel model for vGPCR-mediated oncogenesis will contribute to our understanding of the role of vGPCR in the pathogenesis of HHV-8 and may even be important in identifying critical molecular and epigenetic changes during tumor progression in vivo. AU - Thirunarayanan, N.* AU - Cifire, F.* AU - Fichtner, I.* AU - Posner, S.* AU - Benga, J.* AU - Reiterer, P.* AU - Kremmer, E. AU - Kölble, K.* AU - Lipp, M.* C1 - 178 C2 - 24796 SP - 5702-5712 TI - Enhanced tumorigenicity of fibroblasts transformed with human herpesvirus 8 chemokine receptor vGPCR by successive passage in nude and immunocompetent mice. JO - Oncogene VL - 26 IS - 39 PB - Nature Publ. Group PY - 2007 SN - 0950-9232 ER - TY - JOUR AB - Functional inactivation of transcription factors in hematopoietic stem cell development is involved in the pathogenesis of acute myeloid leukemia (AML). Stem cell regulator C/enhancer binding protein (EBP)alpha is among such transcription factors known to be inactive in AML. This is either due to mutations or inhibition by protein-protein interactions. Here, we applied a mass spectrometry-based proteomic approach to systematically identify putative co-activator proteins interacting with the DNA-binding domain (DBD) of C/EBP transcription factors. In our proteomic screen, we identified c-Jun N-terminal kinase (JNK) 1 among others such as PAK6, MADP-1, calmodulin-like skin proteins and ZNF45 as proteins interacting with DBD of C/EBPs from nuclear extract of myelomonocytic U937 cells. We show that kinase JNK1 physically interacts with DBD of C/EBP alpha in vitro and in vivo. Furthermore, we show that active JNK1 inhibits ubiquitination of C/EBP alpha possibly by phosphorylating in its DBD. Consequently, JNK1 prolongs C/EBP alpha protein half-life leading to its enhanced transactivation and DNA-binding capacity. In certain AML patients, however, the JNK1 mRNA expression and its kinase activity is decreased which suggests a possible reason for C/EBP alpha inactivation in AML. Thus, we report the first proteomic screen of C/EBP-interacting proteins, which identifies JNK1 as positive regulator of C/EBP alpha. AU - Trivedi, A.K.* AU - Bararia, D.* AU - Christopeit, M.* AU - Peer Zada, A.A. AU - Singh, S.M.* AU - Kieser, A. AU - Hiddemann, W.* AU - Behre, H.M.* AU - Behre, G.* C1 - 2681 C2 - 24152 SP - 1789-1801 TI - Proteomic identification of C/EBP-DBD multiprotein complex: JNK1 activates stem cell regulator C/EBPalpha by inhibiting its ubiquitination. JO - Oncogene VL - 26 IS - 12 PY - 2007 SN - 0950-9232 ER - TY - JOUR AU - Djafarzadeh, R.* AU - Nößner, E. AU - Engelmann, H.* AU - Schendel, D.J. AU - Notohamiprodjo, M.* AU - von Luettichau, I.* AU - Nelson, P.J.* C1 - 4831 C2 - 23935 SP - 1496-1508 TI - GPI-anchored TIMP-1 treatment renders renal cell carcinoma sensitive to FAS-mediated killing. JO - Oncogene VL - 25 PY - 2006 SN - 0950-9232 ER - TY - JOUR AU - Dolznig Grebien, F.* AU - Deiner, E.M.* AU - Stangl, K.* AU - Kolbus, A.* AU - Habermann, B.* AU - Kerenyi, M.A.* AU - Kieslinger, M. AU - Moriggl, R.* AU - Beug, H.* AU - Müllner, E.W.* C1 - 4938 C2 - 23899 SP - 2890-2900 TI - Erythroid progenitor renewal versus differentiation: Genetic evidence for cell autonomous, essential functions of EpoR, STat5 and the GR. JO - Oncogene VL - 25 PY - 2006 SN - 0950-9232 ER - TY - JOUR AU - Fröhlich Archangelo, L.* AU - Gläsner, J.* AU - Krause, A.* AU - Bohlander, S.K. C1 - 4187 C2 - 23980 SP - 4099-4109 TI - The novel CALM interactor CATS influences the subcellular localization of the leukemogenic fusion protein CALM/AF10. JO - Oncogene VL - 25 PY - 2006 SN - 0950-9232 ER - TY - JOUR AU - Pazzaglia, S.* AU - Tanori, M.* AU - Mancuso, M.* AU - Rebessi, S.* AU - Leonardi, S.* AU - di Majo, V.* AU - Covelli, V.* AU - Atkinson, M.J. AU - Hahn, H.* AU - Saran, A.* C1 - 5186 C2 - 23652 SP - 1165-1173 TI - Linking DNA damage to medulloblastoma tumorigenesis in patched heterozygous knockout mice. JO - Oncogene VL - 25 PY - 2006 SN - 0950-9232 ER - TY - JOUR AU - Dirmeier, U. AU - Hoffmann, R.* AU - Kilger, E. AU - Schultheiss, U.* AU - Briseño, C. AU - Gires, O. AU - Kieser, A. AU - Eick, D. AU - Sugden, B.* AU - Hammerschmidt, W. C1 - 4305 C2 - 22596 SP - 1711-1717 TI - Latent membrane protein 1 of Epstein-Barr virus coordinately regulates proliferation with control of apoptosis. JO - Oncogene VL - 24 PY - 2005 SN - 0950-9232 ER - TY - JOUR AU - Weiss, C.* AU - Faust, D.* AU - Dürk, H.* AU - Kolluri, S.K.* AU - Pelzer, A.* AU - Schneider, S.* AU - Dietrich, C.* AU - Oesch, F.* AU - Göttlicher, M. C1 - 4208 C2 - 22840 SP - 4975-4983 TI - TCDD induces c-jun expression via a novel Ah (dioxin) receptor-mediated p38-MAPK-dependent pathway. JO - Oncogene VL - 24 PY - 2005 SN - 0950-9232 ER - TY - JOUR AU - Yu, M.* AU - Schreck, S.* AU - Cerni, Ch.* AU - Schamberger, Ch.* AU - Lesniewicz, K.* AU - Poreba, E.* AU - Vervoorts, J.* AU - Walsemann, G.* AU - Grötzinger, J.* AU - Kremmer, E. AU - Mehraein, Y.* C1 - 4302 C2 - 23025 SP - 1982-1993 TI - PARP-10, a novel Myc-interacting protein with poly(ADP-ribose) polymerase activity, inhibits transformation. JO - Oncogene VL - 24 PY - 2005 SN - 0950-9232 ER - TY - JOUR AU - Kappler, R.* AU - Bauer, R.* AU - Calzada-Wack, J. AU - Rosemann, M. AU - Hemmerlein, B.* AU - Hahn, H.* C1 - 5172 C2 - 22206 SP - 8785-8795 TI - Profiling the molecular difference between Patched- and p53-dependent rhabdomyosarcoma. JO - Oncogene VL - 23 IS - 54 PY - 2004 SN - 0950-9232 ER - TY - JOUR AU - Münz, M. AU - Kieu, C.* AU - Mack, B.* AU - Schmitt, B.* AU - Zeidler, R.* AU - Gires, O. C1 - 3223 C2 - 22025 SP - 5748-5758 TI - The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation. JO - Oncogene VL - 23 PY - 2004 SN - 0950-9232 ER - TY - JOUR AU - Schlosser, I. AU - Hölzel, M. AU - Hoffmann, R.* AU - Burtscher, H.* AU - Kohlhuber, F. AU - Schuhmacher, M. AU - Chapman, R.D. AU - Weidle, U.H.* AU - Eick, D. C1 - 3368 C2 - 22326 SP - 1-5 TI - Dissection of transcriptional programmes in response to serum and c-Myc in a human B-cell line. JO - Oncogene VL - 24 IS - 3 PY - 2004 SN - 0950-9232 ER - TY - JOUR AB - Overexpression of proto-oncogene c-jun and constitutive activation of the Jun N-terminal kinase (JNK) signaling pathway have been implicated in the leukemic transformation process. However, c-jun expression and the role of the JNK signaling pathway have not been investigated in primary acute myeloid leukemia (AML) cells with frequently observed balanced rearrangements such as t(8;21). In the present study, we report elevated c-jun mRNA expression in AML patient bone marrow cells with t(8;21), t(15;17) or inv(16), and a high correlation in mRNA expression levels of AML1-ETO and c-jun within t(8;21)-positive AML patient cells. In myeloid U937 cells, c-jun mRNA and protein expression increase upon inducible expression of AML1-ETO. AML1-ETO transactivates the human c-jun promoter through the proximal activator protein (AP-1) site by activating the JNK pathway. Overexpression of JNK-inhibitor JIP-1 and chemical JNK inhibitors reduce the transactivation capacity of AML1-ETO on the c-jun promoter and the proapoptotic function of AML1-ETO in U937 cells. An autocrine mechanism involving granulocyte-colony stimulating factor (G-CSF) and G-CSF receptor (G-CSF-R) might participate in AML1-ETO mediated JNK-signaling, because AML1-ETO induces G-CSF and G-CSF-R expression, and G-CSF-R-neutralizing antibodies reduce AML1-ETO-induced JNK phosphorylation. These data suggest a model in which AML1-ETO induces proto-oncogene c-jun expression via the proximal AP-1 site of the c-jun promoter in a JNK-dependent manner. AU - Elsässer, A. AU - Franzen, M. AU - Kohlmann, A. AU - Weisser, M. AU - Schnittger, S. AU - Schoch, C. AU - Reddy, V.A. AU - Burel, S. AU - Zhang, D.E.* AU - Ueffing, M. AU - Tenen, D.G.* AU - Hiddemann, W. AU - Behre, G. C1 - 22429 C2 - 31086 SP - 5646-57 TI - The fusion protein AML1-ETO in acute myeloid leukemia with translocation t(8;21) induces c-jun protein expression via the proximal AP-1 site of the c-jun promoter in an indirect, JNK-dependent manner. JO - Oncogene VL - 22 IS - 36 PY - 2003 SN - 0950-9232 ER - TY - JOUR AU - Rangiata, J.* AU - Vangala, R.K.* AU - Singh, S.M.* AU - Zada, A.A.P.* AU - Elsässer, A. AU - Kohlmann, A. AU - Haferlach, T. AU - Tenen, D.G.* AU - Hiddemann, W. AU - Behre, G. C1 - 9959 C2 - 21607 SP - 4760-4764 TI - Elevated c-Jun expression in acute myeloid leukemias inhibits C/EBPalpha DNA binding via leucine zipper domain interaction. JO - Oncogene VL - 22 PY - 2003 SN - 0950-9232 ER - TY - JOUR AU - Zada, A.A.P.* AU - Singh, S.M.* AU - Reddy, V.A.* AU - Elsässer, A. AU - Meisel, A.* AU - Haferlach, T. AU - Tenen, D.G.* AU - Hiddemann, W. AU - Behre, G. C1 - 9958 C2 - 21606 SP - 2296-2308 TI - Downregulation of c-Jun expression and cell cycle regulatory molecules in acute myeloid leukemia cells upon CD44 ligation. JO - Oncogene VL - 22 PY - 2003 SN - 0950-9232 ER - TY - JOUR AU - Nathrath, M. AU - Kuosaite, V. AU - Rosemann, M. AU - Kremer, M.* AU - Poremba, Ch.* AU - Wakana, S.* AU - Yanagi, M. AU - Nathrath, W.B.J.* AU - Höfler, H. AU - Imai, K. AU - Atkinson, M.J. C1 - 9960 C2 - 20477 SP - 5975-5980 TI - Two novel tumor suppressor gene loci on chromosome 6q and 15q in human osteosarcoma identified through comparative study of allelic imbalances in mouse and man. JO - Oncogene VL - 21 PY - 2002 SN - 0950-9232 ER - TY - JOUR AU - Pazzaglia, S.* AU - Mancuso, M.* AU - Atkinson, M.J. AU - Tanori, M.* AU - Rebessi, S.* AU - di Majo, V.* AU - Covelli, V.* AU - Hahn, H.* AU - Saran, A.* C1 - 9961 C2 - 20647 SP - 7580-7584 TI - High incidence of medulloblastoma following X-ray-irradiation of newborn Ptc1 heterozygous mice. JO - Oncogene VL - 21 PY - 2002 SN - 0950-9232 ER - TY - JOUR AU - Vecsey-Semjen, B.* AU - Becker, K.-F. AU - Sinski, A.* AU - Blennow, E.* AU - Vietor, I.* AU - Zatloukal, K.* AU - Beug, H.* AU - Wagner, E.* AU - Huber, L.A.* C1 - 21958 C2 - 20478 SP - 4646-4662 TI - Novel colon cancer cell lines leading to better understanding of the diversity of respective primary cancers. JO - Oncogene VL - 21 PY - 2002 SN - 0950-9232 ER - TY - JOUR AU - Lewitzky, M.* AU - Kardinal, Ch.* AU - Gehring, N.H.* AU - Schmidt, E.K.* AU - Konkol, B. AU - Eulitz, M. AU - Birchmeier, W.* AU - Schaeper, U.* AU - Feller, S.M.* C1 - 21765 C2 - 19958 SP - 1052-1062 TI - The C-terminal SH3 domain of the adapter protein Grb2 binds with high affinity to sequences in Gab1 and SlP-76 which lack the SH3-typical P-x-x-P core motif. JO - Oncogene VL - 20 PY - 2001 SN - 0950-9232 ER - TY - JOUR AU - Boese, A.* AU - Sauter, M.* AU - Galli, U.* AU - Best, B.* AU - Herbst, H.* AU - Mayer, J.* AU - Kremmer, E. AU - Roemer, K.* AU - Mueller-Lantzsch, N.* C1 - 21601 C2 - 19732 SP - 4328-4336 TI - Human endogenous retrovirus protein cORF supports cell transformation and associated with the promyelocytic leukemia zinc finger protein. JO - Oncogene VL - 19 PY - 2000 SN - 0950-9232 ER - TY - JOUR AB - Growth factor stimulated receptor tyrosine kinases activate a protein kinase cascade via the serine/threonine protein kinase Raf-1. Direct upstream activators of Raf-1 are Ras and Src. This study shows that MEK1, the direct downstream effector of Raf-1, can also stimulate Raf-1 kinase activity by a positive feedback loop. Activated MEK1 mediates hyperphosphorylation of the amino terminal regulatory as well as of the carboxy terminal catalytic domain of Raf-1. The hyperphosphorylation of Raf-1 correlates with a change in the tryptic phosphopeptide pattern only at the carboxy terminus of Raf-1 and an increase in Raf-1 kinase activity. MEK1-mediated Raf-1 activation is inhibited by co-expression of the MAPK specific phosphatase MKP-1 indicating that the MEK1 effect is exerted through a MAPK dependent pathway. Stimulation of Raf-1 activity by MEK1 is independent of Ras, Src and tyrosine phosphorylation of Raf-1. MEK1 can however synergize with Ras and leads to further increase of the Raf-1 kinase activity. Thus, MEK1 can mediate activation of Raf-1 by a novel positive feedback mechanism which allows fast signal amplification and could prolong activation of Raf-1. AU - Zimmermann, S.* AU - Rommel, C.* AU - Ziogas, A.* AU - Lovric, J. AU - Moelling, K.* AU - Radziwill, G.* C1 - 33854 C2 - 35246 SP - 1503-1511 TI - MEK1 mediates a positive feedback on Raf-1 activity independently of Ras and Src. JO - Oncogene VL - 15 IS - 13 PY - 1997 SN - 0950-9232 ER - TY - JOUR AU - Mautner, J. AU - Behrends, U. AU - Hörtnagel, K. AU - Brielmeier, M. AU - Hammerschmidt, W. AU - Strobl, L.J. AU - Bornkamm, G.W. AU - Polack, A. C1 - 20748 C2 - 17097 SP - 1299-1307 TI - c-myc expression is activated by the immunoglobulin kappa-enhancers from a distance of at least 30 kb but not by elements located within 50 kb of the unaltered c-myc locus in vivo. JO - Oncogene VL - 12 PY - 1996 SN - 0950-9232 ER - TY - JOUR AB - A panel of 18 Burkitt's lymphoma (BL) and nine other cell lines was examined for mutations in the N-terminal transactivation domain of c-Myc. Mutations leading to exchange of amino acids were detected in 13 BL but in none of the control cell lines. Mutations in c-Myc clustered between amino acid positions 57 and 62. Thr-58 and Ser-62 are known phosphorylation sites of c-Myc in vivo. BL cell lines derived from the same tumour revealed different mutations. Mutant cDNAs of the BL cell line Raji differed at 14 positions indicating ongoing mutation of the translocated c-myc during long-term propagation in cell culture. The effect of mutations on transactivation by c-Myc was tested by expression of GAL4/c-Myc fusion proteins in the BL cell line Raji. Mutants with an amino acid exchange at positions 58 or 60 transactivated a reporter gene two- to fivefold weaker than wildtype c-Myc. Thr-58 and Ser-62 were replaced by aspartic acid to mimic constitutively phosphorylated forms of c-Myc. These mutants transactivated two- to three-fold weaker than wildtype c-Myc indicating that a negative charge at positions 58 and/or 62 per se does not enhance transactivation. We propose that mutations in the N-terminal domain of c-Myc correlate with reduced transactivation and provide a growth advantage for BL cells. AU - Albert, T.K. AU - Urlbauer, B. AU - Kohlhuber, F. AU - Hammersen, B. AU - Eick, D. C1 - 40021 C2 - 0 SP - 759-763 TI - Ongoing mutations in the N-terminal domain of c-Myc affect transactivation in Burkitt's lymphoma cell lines. JO - Oncogene VL - 9 IS - 3 PY - 1994 SN - 0950-9232 ER - TY - JOUR AB - A block of RNA elongation in exon 1 of the murine c-myc gene has been described for normal mouse fibroblats, lymphoid and myeloid cell lines and mouse erythroleukemia (MEL) cells. MEL cells differentiate after induction with the chemical agent dimethylsulfoxide (DMSO). The rapid initial down-regulation of c-myc that occurs after treatment with DMSO has been explained by an increase in the block of RNA elongation within the 3′ part of c-myc exon 1. In contrast to these reports, we find that down-regulation of c-myc in DMSO-induced MEL cells occurs at the c-myc P1 and P2 promoters. The P1 promoter is repressed by inhibition of initiation, whereas transcription of P2 RNA is blocked by retention of RNA polymerase II at or close to the P2 promoter. The earlier described block of RNA elongation at a run of five thymidines in the 3′ part of c-myc exon 1 was not observed. AU - Kohlhuber, F. AU - Strobl, L.J. AU - Eick, D. C1 - 33276 C2 - 35481 SP - 1099-1102 TI - Early down-regulation of c-myc in dimethylsulfoxide-induced mouse erythroleukemia (MEL) cells is mediated at the P1/P2 promoters. JO - Oncogene VL - 8 IS - 4 PY - 1993 SN - 0950-9232 ER - TY - JOUR AB - T1 is a glycosylated protein in the carcinoembryonic antigen (CEA) family of tumour marker molecules. It was originally identified by virtue of its transient induction after the expression of p21H-ras in NIH3T3 fibroblasts. Here we show that the T1 gene is activated in mammary adenocarcinomas of transgenic mice harbouring an H-ras transgene under the control of the mammary-specific whey acidic protein (WAP) promoter. By contrast, T1 mRNA was not, or only faintly, detectable in mammary carcinomas of transgenic mice bearing a WAP-myc transgene. Thus, T1 overexpression does not appear to be a general tumour-specific phenomenon. A dependence of T1 gene expression on the action of p21H-ras is suggested by the observation of T1 mRNA in nude mouse tumours generated from H-ras-transformed cultured mammary epithelial cells. Interestingly, activation of the T1 gene is also found during the maturation of the mammary gland (3-4 weeks after birth), whereas it is absent during its terminal differentiation in pregnancy and lactation. This expression pattern suggests a role for the secreted T1 glycoprotein in the phase of epithelial proliferation of the mammary gland. It appears that p21H-ras-induced transformation of mammary epithelial cells mimicks the situation occurring in puberty. In both developmental stages the T1 glycoprotein might affect cell interactions of the proliferating epithelial cells with the surrounding stroma. It might thus promote ductal outgrowth in gland maturation as well as invasive growth of p21H-ras-transformed mammary epithelial cells. AU - Rößler, U. AU - Andres, A.C.* AU - Reichmann, E.* AU - Schmahl, W.G. AU - Werenskiold, A.K. C1 - 33783 C2 - 35460 SP - 609-617 TI - T1, an immunoglobulin superfamily member, is expressed in H-ras-dependent epithelial tumours of mammary cells. JO - Oncogene VL - 8 IS - 3 PY - 1993 SN - 0950-9232 ER - TY - JOUR AB - In the Burkitt's lymphoma (BL) cell line BL67 the first exon of the c-myc gene is fused to the μ-switch region of the immunoglobulin heavy-chain gene (IgH). BL67 cells express IgH/c-myc hybrid RNAs which are initiated in the immunoglobulin locus, transcribed across the chromosomal breakpoint into the first exon of c-myc and spliced using the physiological splice donor and acceptor sites of the c-myc gene. We have isolated cDNAs of these hybrid RNAs and characterized the start points in the Ig heavy-chain gene. Two promoters were identified in the μ-switch region of BL67 cells which give rise to antisense transcription of the μ-gene. These promoters are also active in other BL cell lines, in B cells without Ig translocation and in a T-cell line. Both promoters co-localize with DNAase I-hypersensitive sites, HNF and HSW, in the μ-switch region. The structures of IgH/c-myc hybrid RNAs and of the corresponding promoters are described. AU - Apel, T.W. AU - Mautner, J.M. AU - Polack, A. AU - Bornkamm, G.W. AU - Eick, D. C1 - 40504 C2 - 13129 SP - 1267-1271 TI - Two antisense promoters in the immunoglobulin μ-switch region drive expression of c-myc in the Burkitt's lymphoma cell line BL67. JO - Oncogene VL - 7 IS - 7 PY - 1992 SN - 0950-9232 ER - TY - JOUR AU - Jucker, M. AU - Roebroek, A.J.M. AU - Mautner, J. AU - Koch, K. AU - Eick, D. AU - Diehl, V. AU - van de Ven, W.J.M. AU - Tesch, H. C1 - 19251 C2 - 12322 SP - 943-952 TI - Expression of Truncated Transcripts of the Proto-Oncogene c-fps/fes in Human Lymphoma and Lymphoid Leukemia Cell Lines. JO - Oncogene VL - 7 PY - 1992 SN - 0950-9232 ER - TY - JOUR AU - Polack, A. AU - Strobl, L.J. AU - Feederle, R. AU - Schweizer, M. AU - Koch, E. AU - Eick, D. AU - Wiegand, H. AU - Bornkamm, G.W. C1 - 19173 C2 - 12234 SP - 2033-2040 TI - The Intron Enhancer of the Immunoglobulin Kappa Gene Activates c-myc but does not Induce the Burkitt-Specific Promoter Shift. JO - Oncogene VL - 6 PY - 1991 SN - 0950-9232 ER - TY - JOUR AU - Eick, D. AU - Polack, A. AU - Kofler, E. AU - Lenoir, G.M. AU - Rickinson, A.B. AU - Bornkamm, G.W. C1 - 18207 C2 - 11418 SP - 1397-1402 TI - Expression of P0-and P3-RNA from the Normal and Translocated c-myc Allele in Burkitt's Lymphoma Cells. JO - Oncogene VL - 5 PY - 1990 SN - 0950-9232 ER -