The mammalian Cut homeodomain protein functions as a cell-cycle-dependent transcriptional repressor which downmodulates p21WAF1/CIP1/SDI1 in S phase.
Cut is a homeodomain transcription factor which has the unusual property of containing several DNA-binding domains: three regions called Cut repeats and the Cut homeodomain. Genetic studies in Drosophila melanogaster indicate that cut plays important roles in the determination and maintenance of cell-type specificity. In the present study, we show that mammalian Cut proteins may yet play another biological role, specifically in proliferating cells. We found that the binding of Cut to a consensus binding site varies during the cell cycle. Binding was virtually undetectable in G0 and early G1, but became very strong as cells reached S phase. This was shown to result both from an increase in Cut expression and dephosphorylation of the Cut homeodomain by the Cdc25A phosphatase. We also show that the increase in Cut activity coincides with a decrease in p21WAF1/CIP1/SDI1 mRNAs. In co-transfection experiments, Cut proteins repressed p21WAF1/CIP1/SDI1 gene expression through binding to a sequence that overlaps the TATA box. Moreover, p21WAF1/CIP1/SDI1 expression was repressed equally well by either Cdc25A or Cut. Altogether, these results suggest a model by which Cdc25A activates the Cut repressor which then downregulates transcription of p21WAF1/CIP1/SDI1 in S phase. Thus, in addition to their role during cellular differentiation, Cut proteins also serve as cell-cycle-dependent transcriptional factors in proliferating cells.
Molecular Oncology Group, Royal Victoria Hospital, Quebec, Canada.
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Coqueret
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Bérubé
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Nepveu
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism*; D004247:DNA; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D016193:G1 Phase; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D016196:S Phase; D012694:Serine / Q000378:metabolism; D016385:TATA Box; D014157:Transcription Factors; D014158:Transcription, Genetic; D020687:cdc25 Phosphatases
C493956:CDKN1A protein, human; C080632:CUX1 protein, human; C493957:Cdkn1a protein, mouse; C000624101:Cux1 protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D012694:Serine; D004247:DNA; C517004:CDC25A protein, human; C517005:Cdc25a protein, mouse; D017027:Protein Tyrosine Phosphatases; D020687:cdc25 Phosphatases