The transition from cellular quiescence (G0) into S phase is regulated by the mitogenic-activation of D-type cyclins and cyclin-dependent kinases (Cdks), the sequestration of the Cdk inhibitors (CDKIs), p21 and p27, and the hyperphosphorylation of Rb with release of E2F transcription factors1,2. However, fibroblasts that lack all D-type cyclins can still undergo serum-induced proliferation3 and key E2F targets are expressed at stable levels despite cyclical Rb–E2F activity1. Here, we show that serum induces expression of the Ets transcription factor, Gabpα, and that its ectopic expression induces quiescent cells to re-enter the cell cycle. Genetic disruption of Gabpα prevents entry into S phase, and selectively reduces expression of genes that are required for DNA synthesis and degradation of CDKIs, yet does not alter expression of D-type cyclins, Cdks, Rb or E2Fs. Thus, GABP is necessary and sufficient for re-entry into the cell cycle and it regulates a pathway that is distinct from that of D-type cyclins and CDKs.
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We thank: R. Mortensen (University of Michigan, Ann Arbour, MI) for the pLNCL targeting plasmid; J. Sedivy (Brown University, Providence, RI) for advice on targeting construct strategy; T. Nottoli (Yale University, New Haven, CT) for assistance in generation of floxed Gabpa mice; J. Singer (Brown University) for pBabe–Cre; K.-U. Wagner (University of Nebraska, Omaha, NE) for the retroviral DNA pBabe; J. Foster (University of Tennessee, Knoxville, TN) for the Adeno–Skp2 virus; T. Jacks (Massachussetts Institute of Technology, Cambridge, MA) for Rb−/− MEFs; S. Fleming (Millennium Pharmaceuticals, Cambridge, MA) for technical assistance; E. Sabo (Rhode Island Hospital, Providence, RI) for imaging assistance; and E. Chin and J. Singer (Brown University), J. Licht (Northwestern University, Chicago, IL), D. Tenen (Harvard Medical School, Boston, MA), and members of the Rosmarin laboratory for critical reading of the manuscript. This work was supported by 1R01HL073945, and the following National Institutes of Health (NIH) COBRE Awards: P20 RR15578 (Brown University), 1P20RR017695 (Lifespan, Providence, RI), and 1P20RR018757 (Roger Williams Medical Center, Providence, RI) to A.G.R. Z.-F.Y. is supported by the Herbert W. Savit '49 Fund (Brown University).
Supplementary figures S1, S2, S3 and S4
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Virchows Archiv (2016)