Browsing by Author "Clem, A. L."

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    6-Phosphofructo-2-kinase (PFKFB3) promotes cell cycle progression and suppresses apoptosis via Cdk1-mediated phosphorylation of p27
    (Nature Publishing Group, 2014-07-01) Yalçın, Abdullah; Clem, B. F.; Imbert-Fernandez, Y.; Özcan, Selahattin Can; Peker, Sabire; O'Neal, J.; Klarer, A. C.; Clem, A. L.; Telang, S.; Chesney, J.; YALÇIN, ABDULLAH; Özcan, Selahattin Can; Peker, Sabire; Uludağ Üniversitesi/Veteriner Fakültesi/Biyokimya Anabilim Dalı; Uludağ Üniversitesi/Veteriner Fakültesi/Histoloji ve Embriyoloji Anabilim Dalı; 0000-0001-8519-8375; HKM-4820-2023; ABI-4164-2020; AAA-6938-2022; FUW-0951-2022
    The control of glucose metabolism and the cell cycle must be coordinated in order to guarantee sufficient ATP and anabolic substrates at distinct phases of the cell cycle. The family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4) are well established regulators of glucose metabolism via their synthesis of fructose-2,6-bisphosphate (F2,6BP), a potent allosteric activator of 6-phosphofructo-1-kinase (Pfk-1). PFKFB3 is overexpressed in human cancers, regulated by HIF-1 alpha, Akt and PTEN, and required for the survival and growth of multiple cancer types. Although most functional studies of the role of PFKFB3 in cancer progression have invoked its well-recognized function in the regulation of glycolysis, recent observations have established that PFKFB3 also traffics to the nucleus and that its product, F2,6BP, activates cyclin-dependent kinases (Cdks). In particular, F2,6BP stimulates the Cdk-mediated phosphorylation of the Cip/Kip protein p27 (threonine 187), which in turn results in p27's ubiquitination and proteasomal degradation. As p27 is a potent suppressor of the G1/S transition and activator of apoptosis, we hypothesized that the known requirement of PFKFB3 for cell cycle progression and prevention of apoptosis may be partly due to the ability of F2,6BP to activate Cdks. In this study, we demonstrate that siRNA silencing of endogenous PFKFB3 inhibits Cdk1 activity, which in turn stabilizes p27 protein levels causing cell cycle arrest at G1/S and increased apoptosis in HeLa cells. Importantly, we demonstrate that the increase in apoptosis and suppression of the G1/S transition caused by siRNA silencing of PFKFB3 expression is reversed by co-siRNA silencing of p27. Taken together with prior publications, these observations support a model whereby PFKFB3 and F2,6BP function not only as regulators of Pfk-1 but also of Cdk1 activity, and therefore serve to couple glucose metabolism with cell proliferation and survival in transformed cells.
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    PFKFB2 regulates glycolysis and proliferation in pancreatic cancer cells
    (Springer, 2020-05-27) Özcan, S. C.; Fernandez, Y. I.; Muchut, R. J.; Iglesias, A. A.; Gürpınar, Y.; Clem, A. L.; Chesney, J. A.; Yalçın, A.; Bozkurt, Aybike Sarıoğlu; Altunok, Tuğba Hazal; Akkoç , Ahmet; Güzel, Saime; Güler, Sabire; Bursa Uludağ Üniversitesi/Veterinerlik Fakültesi/Biyokimya Anabilim Dalı.; Bursa Uludağ Üniversitesi/Veterinerlik Fakültesi/Patoloji Anabilim Dalı.; Bursa Uludağ Üniversitesi/Veterinerlik Fakültesi/Histoloji ve Embriyoloji Anabilim Dalı.; 0000-0002-8287-6617; 0000-0003-1263-3799; 0000-0003-0796-5000; S-2474-2018; GCY-0775-2022; DTZ-3578-2022; AAH-4275-2021; HTY-9355-2023; 57216787271; 57216790624; 55584229300; 55460886200; 57198223090
    Tumor cells increase glucose metabolism through glycolysis and pentose phosphate pathways to meet the bioenergetic and biosynthetic demands of rapid cell proliferation. The family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4) are key regulators of glucose metabolism via their synthesis of fructose-2,6-bisphosphate (F2,6BP), a potent activator of glycolysis. Previous studies have reported the co-expression of PFKFB isozymes, as well as the mRNA splice variants of particular PFKFB isozymes, suggesting non-redundant functions. Majority of the evidence demonstrating a requirement for PFKFB activity in increased glycolysis and oncogenic properties in tumor cells comes from studies on PFKFB3 and PFKFB4 isozymes. In this study, we show that the PFKFB2 isozyme is expressed in tumor cell lines of various origin, overexpressed and localizes to the nucleus in pancreatic adenocarcinoma, relative to normal pancreatic tissue. We then demonstrate the differential intracellular localization of two PFKFB2 mRNA splice variants and that, when ectopically expressed, cytoplasmically localized mRNA splice variant causes a greater increase in F2,6BP which coincides with an increased glucose uptake, as compared with the mRNA splice variant localizing to the nucleus. We then show that PFKFB2 expression is required for steady-state F2,6BP levels, glycolytic activity, and proliferation of pancreatic adenocarcinoma cells. In conclusion, this study may provide a rationale for detailed investigation of PFKFB2's requirement for the glycolytic and oncogenic phenotype of pancreatic adenocarcinoma cells.