The Ets transcription factor GABP is required for cell-cycle progression.
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 factors. However, fibroblasts that lack all D-type cyclins can still undergo serum-induced proliferation and key E2F targets are expressed at stable levels despite cyclical Rb-E2F activity. Here, we show that serum induces expression of the Ets transcription factor, Gabpalpha, and that its ectopic expression induces quiescent cells to re-enter the cell cycle. Genetic disruption of Gabpalpha 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.
Yang
Zhong-Fa
ZF
Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912, USA.
Mott
Stephanie
S
Rosmarin
Alan G
AG
D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004256:DNA Polymerase I / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D051268:GA-Binding Protein Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015870:Gene Expression; D019426:Integrases / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008954:Models, Biological; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D051268:GA-Binding Protein Transcription Factor; C495656:Gabpa protein, mouse; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D013940:Thymidylate Synthase; D018844:Cyclin-Dependent Kinases; C045073:Cre recombinase; D019426:Integrases; D004256:DNA Polymerase I