Abstract
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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Cell Cycle / physiology*
-
Cell Line
-
Cell Proliferation
-
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
-
Cyclin-Dependent Kinase Inhibitor p27 / metabolism
-
Cyclin-Dependent Kinases / metabolism
-
Cyclins / metabolism
-
DNA Polymerase I / genetics
-
DNA Polymerase I / metabolism
-
Fibroblasts / metabolism
-
GA-Binding Protein Transcription Factor / genetics
-
GA-Binding Protein Transcription Factor / metabolism
-
GA-Binding Protein Transcription Factor / physiology*
-
Gene Expression
-
Integrases / genetics
-
Mice
-
Mice, Inbred Strains
-
Mice, Transgenic
-
Models, Biological
-
NIH 3T3 Cells
-
Promoter Regions, Genetic
-
S-Phase Kinase-Associated Proteins / genetics
-
S-Phase Kinase-Associated Proteins / metabolism
-
Thymidylate Synthase / genetics
-
Thymidylate Synthase / metabolism
-
Transfection
Substances
-
Cyclin-Dependent Kinase Inhibitor p21
-
Cyclins
-
GA-Binding Protein Transcription Factor
-
Gabpa protein, mouse
-
S-Phase Kinase-Associated Proteins
-
Cyclin-Dependent Kinase Inhibitor p27
-
Thymidylate Synthase
-
Cyclin-Dependent Kinases
-
Cre recombinase
-
Integrases
-
DNA Polymerase I