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6-Phosphofructo-2-kinase (PFKFB3) promotes cell cycle progression and suppresses apoptosis via Cdk1-mediated phosphorylation of p27

dc.contributor.authorYalçın, Abdullah
dc.contributor.authorClem, B. F.
dc.contributor.authorImbert-Fernandez, Y.
dc.contributor.authorÖzcan, Selahattin Can
dc.contributor.authorPeker, Sabire
dc.contributor.authorO'Neal, J.
dc.contributor.authorKlarer, A. C.
dc.contributor.authorClem, A. L.
dc.contributor.authorTelang, S.
dc.contributor.authorChesney, J.
dc.contributor.buuauthorYALÇIN, ABDULLAH
dc.contributor.buuauthorÖzcan, Selahattin Can
dc.contributor.buuauthorPeker, Sabire
dc.contributor.departmentUludağ Üniversitesi/Veteriner Fakültesi/Biyokimya Anabilim Dalı
dc.contributor.departmentUludağ Üniversitesi/Veteriner Fakültesi/Histoloji ve Embriyoloji Anabilim Dalı
dc.contributor.orcid0000-0001-8519-8375
dc.contributor.researcheridHKM-4820-2023
dc.contributor.researcheridABI-4164-2020
dc.contributor.researcheridAAA-6938-2022
dc.contributor.researcheridFUW-0951-2022
dc.date.accessioned2024-08-15T10:58:39Z
dc.date.available2024-08-15T10:58:39Z
dc.date.issued2014-07-01
dc.description.abstractThe 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.
dc.description.sponsorshipEuropean Union Research Executive Agency PIRG06-GA-2009-256523
dc.description.sponsorshipUnited States Department of Defense
dc.description.sponsorshipUnited States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Cancer Institute (NCI) 1R01CA140991 1R01CA149438
dc.description.sponsorshipAmerican Cancer Society RSG-10-021-01CNE
dc.identifier.doi10.1038/cddis.2014.292
dc.identifier.issn2041-4889
dc.identifier.urihttps://doi.org/10.1038/cddis.2014.292
dc.identifier.urihttps://www.nature.com/articles/cddis2014292
dc.identifier.urihttps://hdl.handle.net/11452/44064
dc.identifier.volume5
dc.identifier.wos000341639300028
dc.indexed.wosWOS.SCI
dc.language.isoen
dc.publisherNature Publishing Group
dc.relation.journalCell Death & Disease
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectFructose 2,6-bisphosphate
dc.subjectDecreases glycolysis
dc.subjectHuman brain
dc.subjectP27(kip1)
dc.subject6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase
dc.subjectKinase
dc.subjectCancer
dc.subjectOverexpression
dc.subjectProliferation
dc.subjectApc/c-cdh1
dc.subjectScience & technology
dc.subjectLife sciences & biomedicine
dc.subjectCell biology
dc.title6-Phosphofructo-2-kinase (PFKFB3) promotes cell cycle progression and suppresses apoptosis via Cdk1-mediated phosphorylation of p27
dc.typeArticle
dspace.entity.typePublication
relation.isAuthorOfPublication24332407-6513-4c39-92c2-21a376f853b1
relation.isAuthorOfPublication.latestForDiscovery24332407-6513-4c39-92c2-21a376f853b1

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