TY - JOUR AB - The mRNA translation machinery is tightly regulated through several, at times overlapping, mechanisms that modulate its efficiency and accuracy. Due to their fast rate of growth and metabolism, cancer cells require an excessive amount of mRNA translation and protein synthesis. However, unfavorable conditions, such as hypoxia, amino acid starvation, and oxidative stress, which are abundant in cancer, as well as many anti-cancer treatments inhibit mRNA translation. Cancer cells adapt to the various internal and environmental stresses by employing specialised transcript-specific translation to survive and gain a proliferative advantage. We will highlight the major signaling pathways and mechanisms of translation that regulate the global or mRNA-specific translation in response to the intra- or extra-cellular signals and stresses that are key components in the process of tumourigenesis. AU - Alboushi, L.* AU - Hackett, A.P.* AU - Naeli, P.* AU - Bakhti, M. AU - Jafarnejad, S.M.* C1 - 62141 C2 - 50665 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa TI - Multifaceted control of mRNA translation machinery in cancer. JO - Cell. Signal. VL - 84 PB - Elsevier Science Inc PY - 2021 SN - 0898-6568 ER - TY - JOUR AB - The rapid expansion of the elderly population has led to the recent epidemic of age-related diseases, including increased incidence and mortality of chronic lung diseases, such as Idiopathic Pulmonary Fibrosis (IPF). Cellular senescence is a major hallmark of aging and has a higher occurrence in IPF. The lung epithelium represents a major site of tissue injury, cellular senescence and aberrant activity of developmental pathways such as the WNT/beta-catenin pathway in IPF. The potential impact of WNT/beta-catenin signaling on alveolar epithelial senescence in general as well as in IPF, however, remains elusive. Here, we characterized alveolar epithelial cells of aged mice and assessed the contribution of chronic WNT/beta-catenin signaling on alveolar epithelial type (AT) II cell senescence. Whole lungs from old (16-24 months) versus young (3 months) mice had relatively less epithelial (EpCAM(+)) but more inflammatory (CD45(+)) cells, as assessed by flow cytometry. Compared to young ATII cells, old ATII cells showed decreased expression of the ATII cell marker Surfactant Protein C along with increased expression of the ATI cell marker Hopx, accompanied by increased WNT/beta-catenin activity. Notably, when placed in an organoid assay, old ATII cells exhibited decreased progenitor cell potential. Chronic canonical WNT/beta-catenin activation for up to 7 days in primary ATII cells as well as alveolar epithelial cell lines induced a robust cellular senescence, whereas the non-canonical ligand WNT5A was not able to induce cellular senescence. Moreover, chronic WNT3A treatment of precision-cut lung slices (PCLS) further confirmed ATII cell senescence. Simultaneously, chronic but not acute WNT/beta-catenin activation induced a profibrotic state with increased expression of the impaired ATII cell marker Keratin 8. These results suggest that chronic WNT/beta-catenin activity in the IPF lung contributes to increased ATII cell senescence and reprogramming. In the fibrotic environment, WNT/beta-catenin signaling thus might lead to further progenitor cell dysfunction and impaired lung repair. AU - Lehmann, M. AU - Hu, Q. AU - Hu, Y.* AU - Hafner, K. AU - Costa, R. AU - van den Berg, A. AU - Königshoff, M. C1 - 58600 C2 - 48432 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa TI - Chronic WNT/β-catenin signaling induces cellular senescence in lung epithelial cells. JO - Cell. Signal. VL - 70 PB - Elsevier Science Inc PY - 2020 SN - 0898-6568 ER - TY - JOUR AB - AMP-activated protein kinase (AMPK) is a key regulator of cellular energy homeostasis, acting as a sensor of energy and nutrient status. As such, AMPK is considered a promising drug target for treatment of medical conditions particularly associated with metabolic dysfunctions. To better understand the downstream effectors and physiological consequences of AMPK activation, we have employed a chemical genetic screen in mouse primary hepatocytes in an attempt to identify novel AMPK targets. Treatment of hepatocytes with a potent and specific AMPK activator 991 resulted in identification of 65 proteins phosphorylated upon AMPK activation, which are involved in a variety of cellular processes such as lipid/glycogen metabolism, vesicle trafficking, and cytoskeleton organisation. Further characterisation and validation using mass spectrometry followed by immunoblotting analysis with phosphorylation site-specific antibodies identified AMPK-dependent phosphorylation of Gapex-5 (also known as GTPase-activating protein and VPS9 domain-containing protein 1 (GAPVD1)) on Ser902 in hepatocytes and starch-binding domain 1 (STBD1) on Ser175 in multiple cells/tissues. As new promising roles of AMPK as a key metabolic regulator continue to emerge, the substrates we identified could provide new mechanistic and therapeutic insights into AMPK-activating drugs in the liver. AU - Ducommun, S.* AU - Deak, M.* AU - Zeigerer, A. AU - Göransson, O.* AU - Seitz, S. AU - Collodet, C.* AU - Madsen, A.B.* AU - Jensen, T.E.* AU - Viollet, B.* AU - Foretz, M.* AU - Gut, P.* AU - Sumpton, D.* AU - Sakamoto, K.* C1 - 55526 C2 - 46317 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 45-57 TI - Chemical genetic screen identifies Gapex-5/GAPVDI and STBD1 as novel AMPK substrates. JO - Cell. Signal. VL - 57 PB - Elsevier Science Inc PY - 2019 SN - 0898-6568 ER - TY - JOUR AB - Immunofluorescent staining is a widespread tool in basic science to understand organ morphology and (patho-) physiology. The analysis of imaging data is often performed manually, limiting throughput and introducing human bias. Quantitative analysis is particularly challenging for organs with complex structure such as the kidney. In this study we present an approach for automatic quantification of fluorescent markers and histochemical stainings in whole organ sections using open source software. We validate our novel method in multiple typical challenges of basic kidney research and demonstrate its general relevance and applicability to other complex solid organs for a variety of different markers and stainings. Our newly developed software tool "AQUISTO", applied as a standard in primary data analysis, facilitates efficient large scale evaluation of cellular populations in various types of histological samples. Thereby it contributes to the characterization and understanding of (patho-) physiological processes. AU - Kessel, F.* AU - Steglich, A.* AU - Tschongov, T.* AU - Gembardt, F.* AU - Ruhnke, L.* AU - Stumpf, J.* AU - Behrendt, R.* AU - Cohrs, C.M. AU - Kopaliani, I.* AU - Todorov, V.* AU - Gerlach, M.* AU - Hugo, C.* C1 - 56269 C2 - 46947 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa TI - New automatic quantification method of immunofluorescence and histochemistry in whole histological sections. JO - Cell. Signal. VL - 62 PB - Elsevier Science Inc PY - 2019 SN - 0898-6568 ER - TY - JOUR AB - Recently, a unimolecular Pi-agonist with activity at glucagon-like peptide 1 receptor (GLP-1R), glucose dependent insulinotropic receptor, and the glucagon receptor was reported to improve glycemic control in mice. Here, we defined the underlying molecular mechanisms of enhanced insulin secretion in murine pancreatic islets for a specific tri-agonist. The tii-agonist induced an increase in insulin secretion from murine islets compared to the respective mono-agonists. GLP-1R mainly signals via activation of the G alphas pathway, but inhibition of protein kinase A (H89) and exchange protein activation by cAMP (EPAC) (ESI-09) could not completely block insulin release induced by tri-agonist. Electrophysiological observations identified a strong increase of intracellular Ca2+ concentration and whole-cell currents induced by tri-agonist via transient receptor potential channels (TRPs). Although, EPAC activation mobilizes intracellular Ca2+ via TRPs, the TRPs blockers (La3+ and Ruthenium Red) had a larger inhibitory impact than ESI-09 on tri-agonist stimulatory effects. To test for other potential mechanisms, we blocked PLC activity (U73122) which reduced the superior effect of tri-agonist to induce insulin secretion, and partially inhibited the induced Ca2+ influx. This result suggests that the relative effect of tri-agonist on insulin secretion caused by GLP-1R agonism is mediated mainly via G alphas signaling and partially by activation of PLC. Therefore, the large portion of the increased intracellular Ca2+ concentration and the enhanced whole-cell currents induced by tri-agonist might be attributable to TRP channel activation resulting from signaling through multiple G-proteins. Here, we suggest that broadened intracellular signaling may account for the superior in vivo effects observed with tri-agonism. AU - Khajavi, N.* AU - Finan, B. AU - Kluth, O.* AU - Müller, T.D. AU - Mergler, S.* AU - Schulz, A.* AU - Kleinau, G.* AU - Scheerer, P.* AU - Schürmann, A.* AU - Gudermann, T.* AU - Tschöp, M.H. AU - Krude, H.* AU - DiMarchi, R.D.* AU - Biebermann, H.* C1 - 54021 C2 - 45208 CY - 360 Park Ave South, New York, Ny 10010-1710 Usa SP - 13-22 TI - An incretin-based tri-agonist promotes superior insulin secretion from murine pancreatic islets via PLC activation. JO - Cell. Signal. VL - 51 PB - Elsevier Science Inc PY - 2018 SN - 0898-6568 ER - TY - JOUR AB - The tyrosine kinase inhibitor sunitinib is used for the treatment of numerous cancers in humans. In diabetic patients, sunitinib lowers blood glucose levels and improves glycaemic control. This study aims to analyse whether sunitinib has specific and direct effects on insulin secreting β-cells. Regulation of insulin secretion, of cellular cAMP levels and activation of signalling pathways were examined upon exposure of rat insulinoma INS-1E cells to sunitinib under specific stimulatory and inhibitory conditions. Secreted insulin and cellular cAMP levels were measured using RIA and ELISA, respectively. Protein phosphorylations were examined on western blots. Sunitinib enhanced glucose-induced insulin secretion (GIIS) concentration-dependently, reaching a maximal stimulation at 2μM. Sunitinib further augmented insulin secretion in the presence of elevated cAMP levels and the FFAR1 agonists. Adrenaline and the PKA inhibitor H89 counteracted the stimulatory effect of sunitinib on secretion. However, sunitinib altered neither the cellular levels of cAMP nor the phosphorylation of PKA. Sunitinib did not reduce IGF-1-induced phosphorylation of AKT/PKB and ERK1/2. In conclusion, these results suggest that sunitinib stimulates GIIS by a direct effect on β-cells, which may contribute to the glucose-lowering action of the tyrosine kinase inhibitor in humans. AU - Lutz, S.Z. AU - Ullrich, A.* AU - Häring, H.-U. AU - Ullrich, S. AU - Gerst, F. C1 - 51016 C2 - 43037 CY - New York SP - 91-97 TI - Sunitinib specifically augments glucose-induced insulin secretion. JO - Cell. Signal. VL - 36 PB - Elsevier Science Inc PY - 2017 SN - 0898-6568 ER - TY - JOUR AB - The tumour necrosis factor receptor 1 (TNFR1) activates prosurvival pathways by induction of the NFkappaB pathway and induces cell death via apoptosis. The ubiquitin-conjugating enzyme, Ubc13, mediates the ubiquitylation-dependent formation of protein complexes crucial for the activation and regulation of both pathways. We describe a new role for Ubc13 in the regulation of TNFR1 activity after UV stimulation. Depletion of Ubc13 by RNAi produced a decreased NFkappaB activity and increased apoptosis after stimulation by TNFalpha and UV-C light. These results are consistent with the function of Ubc13 in the ubiquitylation of RIP1, which controls the proapoptotic or prosurvival response after TNFR1 activation. Moreover, we demonstrated that UV-C light induces a close interaction between the Ubc13 protein and the TNFR1 receptor. In the absence of Ubc13 TNFR1 clustering was increased. We conclude that Ubc13 has a regulatory role for the activation of TNFR1 and hence, apoptotic cell death. Thus, our results elucidated a new role for Ubc13 in the regulation of prosurvival or proapoptotic processes, which is upstream of so far investigated functions. AU - Angermeier, M. AU - Eckardt-Schupp, F. AU - Mörtl, S. C1 - 2867 C2 - 27945 SP - 1388-1396 TI - A novel function of Ubc13 in TNFR1 receptor activation. JO - Cell. Signal. VL - 22 IS - 9 PB - Elsevier PY - 2010 SN - 0898-6568 ER - TY - JOUR AB - NBS1 is a member of the Mre11-Rad50-NBS1 complex, which plays a role in cellular responses to DNA damage and the maintenance of genomic stability. Transgenic mice models and clinical symptoms of NBS patients have shown that NBS1 exerts pleiotropic actions on the growth and development of mammals. The present study showed that after repression of endogenous NBS1 levels using short interfering RNA, hTERT-RPE cells demonstrated impaired proliferation and a poor response to IGF-1. NBS1 down-regulated cells displayed disturbances in periodical oscillations of cyclin E and A and delayed cell cycle progression. Remarkably, lower phosphorylation levels of c-Raf and diminished activity of Erk1/2 in response to IGF-1 suggest a link among NBS1, IGF-1 signaling and the Ras/Raf/MEK/ERK cascade. The functional relevance of NBS1 in mitogenic signaling and initiation of cell cycle progression were demonstrated in NBS1 down-regulated cells where IGF-1 had a limited ability to induce the FOS and CCND1 expressions. In conclusion, our findings provide strong evidence that NBS1 has a functional role in IGF-1 signaling for the promotion of cell proliferation via the Ras/Raf/MEK/ERK cascade. AU - Hematulin, A. AU - Sagan, D. AU - Eckardt-Schupp, F. AU - Mörtl, S. C1 - 493 C2 - 25747 SP - 2276-2285 TI - NBS1 is required for IGF-1 induced cellular proliferation through the Ras/Raf/MEK/ERK cascade. JO - Cell. Signal. VL - 20 IS - 2 PB - Elsevier PY - 2008 SN - 0898-6568 ER -