TY - JOUR AB - Humans and primates are long-lived animals with long reproductive phases. One factor that appears to contribute to longevity and fertility in humans, as well as to cancer-free survival, is the transcription factor and tumor suppressor p53, controlled by its main negative regulator MDM2. However, p53 and MDM2 homologs are found throughout the metazoan kingdom from Trichoplacidae to Hominidae. Therefore the question arises, if p53/MDM2 contributes to the shaping of primate features, then through which mechanisms. Previous findings have indicated that the appearances of novel p53-regulated genes and wild-type p53 variants during primate evolution are important in this context. Here, we report on another mechanism of potential relevance. Human endogenous retrovirus K subgroup HML-2 (HERV-K(HML-2)) type 1 proviral sequences were formed in the genomes of the predecessors of contemporary Hominoidea and can be identified in the genomes of Nomascus leucogenys (gibbon) up to Homo sapiens. We previously reported on an alternative splicing event in HERV-K(HML-2) type 1 proviruses that can give rise to nuclear protein of 9 kDa (Np9). We document here the evolution of Np9-coding capacity in human, chimpanzee and gorilla, and show that the C-terminal half of Np9 binds directly to MDM2, through a domain of MDM2 that is known to be contacted by various cellular proteins in response to stress. Np9 can inhibit the MDM2 ubiquitin ligase activity towards p53 in the cell nucleus, and can support the transactivation of genes by p53. Our findings point to the possibility that endogenous retrovirus protein Np9 contributes to the regulation of the p53-MDM2 pathway specifically in humans, chimpanzees and gorillas. AU - Heyne, K.* AU - Kölsch, K.* AU - Bruand, M.* AU - Kremmer, E. AU - Grässer, F.A.* AU - Mayer, J.* AU - Roemer, K.* C1 - 45469 C2 - 37343 SP - 2619-2633 TI - Np9, a cellular protein of retroviral ancestry restricted to human, chimpanzee and gorilla, binds and regulates ubiquitin ligase MDM2. JO - Cell Cycle VL - 14 IS - 16 PY - 2015 SN - 1538-4101 ER - TY - JOUR AB - Diabetes mellitus type 2 (T2DM), insulin therapy, and hyperinsulinemia are independent risk factors of liver cancer. Recently, the use of a novel inhibitor of insulin degrading enzyme (IDE) was proposed as a new therapeutic strategy in T2DM. However, IDE inhibition might stimulate liver cell proliferation via increased intracellular insulin concentration. The aim of this study was to characterize effects of inhibition of IDE activity in HepG2 hepatoma cells and to analyze liver specific expression of IDE in subjects with T2DM. HepG2 cells were treated with 10 nM insulin for 24 h with or without inhibition of IDE activity using IDE RNAi, and cell transcriptome and proliferation rate were analyzed. Human liver samples (n=22) were used for the gene expression profiling by microarrays. In HepG2 cells, IDE knockdown changed expression of genes involved in cell cycle and apoptosis pathways. Proliferation rate was lower in IDE knockdown cells than in controls. Microarray analysis revealed the decrease of hepatic IDE expression in subjects with T2DM accompanied by the downregulation of the p53-dependent genes FAS and CCNG2, but not by the upregulation of proliferation markers MKI67, MCM2 and PCNA. Similar results were found in the liver microarray dataset from GEO Profiles database. In conclusion, IDE expression is decreased in liver of subjects with T2DM which is accompanied by the dysregulation of p53 pathway. Prolonged use of IDE inhibitors for T2DM treatment should be carefully tested in animal studies regarding its potential effect on hepatic tumorigenesis. AU - Pivovarova, O.* AU - von Loeffelholz, C.* AU - Ilkavets, I.* AU - Sticht, C.* AU - Zhuk, S.* AU - Murahovschi, V.* AU - Lukowski, S.* AU - Döcke, S.* AU - Kriebel, J. AU - de Las Heras Gala, T. AU - Malashicheva, A.* AU - Kostareva, A.* AU - Lock, J.F.* AU - Stockmann, M.* AU - Grallert, H. AU - Gretz, N.* AU - Dooley, S.* AU - Pfeiffer, A.F.* AU - Rudovich, N.N.* C1 - 45086 C2 - 37205 CY - Philadelphia SP - 2293-2300 TI - Modulation of insulin degrading enzyme activity and liver cell proliferation. JO - Cell Cycle VL - 14 IS - 14 PB - Taylor & Francis Inc PY - 2015 SN - 1538-4101 ER - TY - JOUR AU - Rosemann, M. AU - Atkinson, M.J. C1 - 43966 C2 - 36732 CY - Philadelphia TI - Spots, Damn'd spots and γH2AX foci. JO - Cell Cycle VL - 14 IS - 7 PB - Taylor & Francis Inc PY - 2015 SN - 1538-4101 ER - TY - JOUR AB - Maintenance of genome integrity relies on multiple DNA repair pathways as well as on checkpoint regulation. Activation of the checkpoint kinases Chk1 and Chk2 by DNA damage triggers cell cycle arrest and improved DNA repair, or apoptosis in case of excessive damage. Chk1 and Chk2 have been reported to act in a complementary or redundant fashion, depending on the physiological context. During secondary immunoglobulin (Ig) diversification in B lymphocytes, DNA damage is abundantly introduced by activation-induced cytidine deaminase (AID) and processed to mutations in a locus-specific manner by several error-prone DNA repair pathways. We have previously shown that Chk1 negatively regulates Ig somatic hypermutation by promoting error-free homologous recombination and Ig gene conversion. We now report that Chk2 shows opposite effects to Chk1 in the regulation of these processes. Chk2 inactivation in B cells leads to decreased Ig hypermutation and Ig class switching, and increased Ig gene conversion activity. This is linked to defects in non-homologous end joining and increased Chk1 activation upon interference with Chk2 function. Intriguingly, in the context of physiological introduction of substantial DNA damage into the genome during Ig diversification, the 2 checkpoint kinases thus function in an opposing manner, rather than redundantly or cooperatively. AU - Davari, K.* AU - Frankenberger, S. AU - Schmidt, A.* AU - Tomi, N.S.* AU - Jungnickel, B.* C1 - 43057 C2 - 35931 CY - Austin SP - 3659-3669 TI - Checkpoint kinase 2 is required for efficient immunoglobulin diversification. JO - Cell Cycle VL - 13 IS - 23 PB - Landes Bioscience PY - 2014 SN - 1538-4101 ER - TY - JOUR AU - Hennig, J. AU - Gebauer, F.* AU - Sattler, M. C1 - 42920 C2 - 35862 CY - Austin SP - 3619-3620 TI - Breaking the protein-RNA recognition code. JO - Cell Cycle VL - 13 IS - 23 PB - Landes Bioscience PY - 2014 SN - 1538-4101 ER - TY - JOUR AB - Neither the molecular mechanisms whereby cancer cells intrinsically are or become resistant to the DNA-damaging agent cisplatin nor the signaling pathways that account for cisplatin cytotoxicity have thus far been characterized in detail. In an attempt to gain further insights into the molecular cascades elicited by cisplatin (leading to resistance or underpinning its antineoplastic properties), we comparatively investigated the ability of cisplatin, C2-ceramide and cadmium dichloride, alone or in the presence of an array of mitochondrion-protective agents, to trigger the permeabilization of purified mitochondria. In addition, we compared the transcriptional response triggered by cisplatin, C2-ceramide and cadmium dichloride in non-small cell lung carcinoma A549 cells. Finally, we assessed the capacity of cisplatin, C2-ceramide and cadmium dichloride to reduce the clonogenic potential of a battery of yeast strains lacking proteins involved in the regulation of cell death, DNA damage signaling and stress management. This multipronged experimental approach revealed that cisplatin elicits signaling pathways that are for the most part "private," i.e., that manifest limited overlap with the molecular cascades ignited by other inducers of mitochondrial apoptosis, and triggers apoptosis mainly in a transcription-independent fashion. Indeed, bona fide cisplatin-response modifiers that we have recently identified by a functional genome-wide siRNA screen are either not transcriptionally regulated during cisplatin-induced cell death or their transcriptional modulation reflects the activation of an adaptive response promoting cisplatin resistance. AU - Galluzzi, L.* AU - Vitale, I.* AU - Senovilla, L.* AU - Eisenberg, T.* AU - Carmona-Gutierrez, D.* AU - Vacchelli, E.* AU - Robert, T.* AU - Ripoche, H.* AU - Jägemann, N. AU - Paccard, C.* AU - Servant, N.* AU - Hupé, P.* AU - Lazar, V.* AU - Dessen, P.* AU - Barillot, E.* AU - Zischka, H. AU - Madeo, F.* AU - Kroemer, G.* C1 - 10468 C2 - 30224 SP - 3472-3480 TI - Independent transcriptional reprogramming and apoptosis induction by cisplatin. JO - Cell Cycle VL - 11 IS - 18 PB - Landes Bioscience PY - 2012 SN - 1538-4101 ER - TY - JOUR AB - Cyclin-dependent kinase-9 (CDK9) plays a central role in transcriptional elongation and controls multiple cotranscriptional histone modifications, including histone H2B monoubiquitination (H2Bub1). Like other CDK9-dependent histone modifications, the role of CDK9 in maintaining H2Bub1 was shown to be partially dependent upon the phosphorylation status of Ser2 of the RNA polymerase II (RNAPII) C-terminal domain (CTD). Since mutation of Ser2 within the RNAPII CTD resulted in a milder effect on H2Bub1 compared with CDK9 knockdown, we explored whether another CDK9 target may also influence H2Bub1. Based on its homology to yeast Bur1, we hypothesized that CDK9 may directly phosphorylate and activate the ubiquitin-conjugating enzyme utilized for H2B monoubiquitination. Indeed, we demonstrate that UBE2A specifically interacts with CDK9, but not CDK2. Furthermore, UBE2A is phosphorylated by CDK9 in vitro and increases UBE2A activity. Interestingly, CDK9 knockdown not only decreases UBE2A phosphorylation and H2Bub1, but also significantly impairs the induction of UBE2A-dependent monoubiquitination of proliferating cell nuclear antigen (PCNA). Thus, we provide the first evidence that CDK9 is required for the activity of UBE2A in humans, and that its activity is not only required for maintaining H2Bub1, but also for the monoubiquitination of PCNA. The common involvement of these two ubiquitinations in distinct DNA repair pathways may provide a mechanistic rationale for further exploring CDK9 as a combinatorial target for increasing the efficacy of existing cancer therapies based on the induction of DNA damage and are repaired by mechanisms which require H2Bub1 and/or PCNA ubiquitination. AU - Shchebet, A.* AU - Karpiuk, O.* AU - Kremmer, E. AU - Eick, D. AU - Johnsen, S.A.* C1 - 7580 C2 - 30135 SP - 2122-2127 TI - Phosphorylation by cyclin-dependent kinase-9 controls ubiquitin-conjugating enzyme-2A function. JO - Cell Cycle VL - 11 IS - 11 PB - Landes Bioscience PY - 2012 SN - 1538-4101 ER - TY - JOUR AB - In mantle cell lymphoma (MCL), overexpression of cyclin D1 is the hallmark of malignant transformation and results from it's juxtaposition to the immunoglobulin heavy chain enhancer. In addition, genomic deletions or point mutations leading to premature truncation of the cyclin D1 3' untranslated region (UTR) have been reported in a several MCL patients as well as in cell lines isolated from various tumors types. We demonstrate that the expression of cyclin D1 with or without the 3'UTR has different phenotypic consequences in stably transduced fibroblasts, with the hyper-proliferative phenotype of cyclin D1 closely linked to the deletion of its 3'UTR. In our study, the loss of the cyclin D1 3'UTR led to a significant upregulation of the protein. However, the loss of AU-rich elements (AREs) from the cyclin D1 3'UTR results in a significant decrease in cyclin D1 protein and UTR-tagged reporter expression. In contrast, the levels of cyclin D1 protein can be significantly reduced by microRNAs of the miR-15/16 family and the miR17-92 cluster that directly target the cyclin D1 3'UTR. Most importantly, these microRNAs regulated the levels of the endogenous cyclin D1 protein encoded by an mRNA with a full 3'UTR but not with 3' UTR deletions. Taken together, our data highlight the regulatory role of the cyclin D1 3'UTR in the expression and phenotype of cyclin D1 and suggest that in MCL and solid tumors with cyclin D1 3'UTR mutations, the loss of microRNA target sites, rather than ARE elements contribute to the pathogenic overexpression of the cyclin D1 protein. AU - Deshpande, A. AU - Pastore, A. AU - Deshpande, A.J. AU - Zimmermann, Y. AU - Hutter, G. AU - Weinkauf, M. AU - Buske, C. AU - Hiddemann, W. AU - Dreyling, M. C1 - 2416 C2 - 26976 SP - 3592-3600 TI - 3'UTR mediated regulation of the cyclin D1 proto-oncogene. JO - Cell Cycle VL - 8 IS - 21 PB - Landes Bioscience PY - 2009 SN - 1538-4101 ER - TY - JOUR AU - Rieger, M. AU - Schroeder, T. C1 - 408 C2 - 26727 SP - 4019-4020 TI - Instruction of lineage choice by hematopoietic cytokines. JO - Cell Cycle VL - 8 IS - 24 PY - 2009 SN - 1538-4101 ER - TY - JOUR AB - Mouse models have demonstrated that both hematopoietic stem cells (HSCs) as well as downstream myeloid progenitors can be targets of transformation in AML. We recently showed in a murine model of the CALM/AF10 fusion gene positive leukemia, that progenitors with lymphoid characteristics can be leukemic stem cell (LSC) candidates in AML. We could demonstrate that the LSC candidate in the CALM/AF10 murine model was positive for the lymphoid associated surface antigen B220, which was not expressed by the leukemic bulk or the normal HSC pool. This offers the intriguing possibility to target the LSCs with antibodies that spare the normal stem cell. AU - Deshpande, A.J. AU - Buske, C. C1 - 4519 C2 - 24702 SP - 543-545 TI - Lymphoid progenitors as candidate cancer stem cells in AML: New perspectives. JO - Cell Cycle VL - 6 IS - 5 PB - Landes Bioscience PY - 2007 SN - 1538-4101 ER - TY - JOUR AU - Jungnickel, B. C1 - 5591 C2 - 24187 SP - 2856-2861 TI - False moves for survival: Error-prone DNA repair in adaptive immunity. JO - Cell Cycle VL - 5 PY - 2006 SN - 1538-4101 ER - TY - JOUR AU - Reindl, C. AU - Spiekermann, K. C1 - 4188 C2 - 23981 SP - 599-602 TI - From kinases to cancer: Leakiness, loss of autoinhibition and leukemia. JO - Cell Cycle VL - 5/6 PY - 2006 SN - 1538-4101 ER - TY - JOUR AB - The discovery of tyrosine kinases that, once deregulated, can cause malignancy, allowed the development of specifically acting anti-cancer compounds. In chronic myeloid leukaemia (CML), the Bcr-Abl kinase inhibitor imatinib (STI571, Gleevec) induces impressive response rates. However, resistance occurs especially in advanced phase CML and Ph + ALL, primarily as a consequence of point mutations within the Bcr-Abl kinase domain that prevent imatinib from binding. To overcome imatinib resistance, alternative Abl kinase inhibitors are finding their way into clinical trials. However, it is likely that resistance to second-generation compounds will occur as well. Therefore, it will be critical to determine specific resistance profiles for each particular compound. We recently devel- oped a cell-based screening strategy that allows one to predict the pattern and relative abundance of Bcr -Abl resistance mutations emerging in the presence of imatinib or an alternative Abl-kinase inhibitor. Using this strategy, the findings in inhibitor resistant sublines reflect observations made in CML patients with imatinib resistance, including Bcr-Abl mutations, amplification of the Bcr-Abl gene, and overexpression of the Bcr-Abl protein. We here provide a detailed methodological description, and discuss the impli- cations of this strategy for different clinically relevant oncogenic tyrosine kinases. AU - von Bubnoff, N.* AU - Barwisch, S.* AU - Speicher, M.R. AU - Peschel, C.* AU - Duyster, J.* C1 - 4065 C2 - 22675 SP - 400-406 TI - A cell-based screening strategy that predicts mutations in oncogenic tyrosine kinases: Implications for clinical resistance in targeted cancer treatment. JO - Cell Cycle VL - 4 IS - 3 PY - 2005 SN - 1538-4101 ER - TY - JOUR AB - Inappropriate control of expression of genetic information is the cause of many forms ofcancer. Aberrant transcriptional repression by recruitment of histone deacetylases (HDACs) isa key step in pathogenesis of myeloid leukemia. We recently reported that development ofcolonic cancer involves alterations in the transcriptional repression machinery by increasedexpression of HDAC 2 upon loss of the APC tumor suppressor. Increased expression ofHDAC 2 is essential for prevention of apoptosis of HT-29 colonic cancer cells. We nowdiscuss whether HDAC 2 also plays a role for aberrant cell cycle regulation and expression ofthe p21Cip/Waf cell cycle inhibitor. Whereas inhibition of HDACs by valproic acid ortrichostatin A increases p21 expression, selective interference with HDAC 2 by siRNAtransfection or reconstitution of wildtype APC does not affect p21 expression. Likewise,treatment of HT-29 cells with the HDAC inhibitor valproic acid leads to a moderate inhibitionof cell cycle progression in the G1 phase whereas interference with HDAC2 expression doesnot. Thus, HDAC 2 appears to serve a preferential role in the prevention of apoptosis and notin cell cycle control similar to the specific importance of HDAC 1 for cell cycle regulation orHDAC 9 for the stress response of the heart. AU - Zhu, P.* AU - Huber, E. AU - Kiefer, F. AU - Göttlicher, M. C1 - 2392 C2 - 22064 SP - 115-117 TI - Specific and redundant functions of histone deacetylases in regulation of cell cycle and apoptosis. JO - Cell Cycle VL - 3 IS - 10 PY - 2004 SN - 1538-4101 ER -