Article: article from journal or magazin.
Involvement of the cell-cycle inhibitor Cip1/WAF1 and the E1A-associated p300 protein in terminal differentiation.
Proceedings of the National Academy of Sciences of the United States of America
The mechanism of cell cycle withdrawal during terminal differentiation is poorly understood. We report here that the cyclin-dependent kinase (CDK) inhibitor p21Cip1/WAF1 is induced at early times of both keratinocyte and myoblast differentiation. p21Cip1/WAF1 induction is accompanied by a drastic inhibition of total Cdk2, as well as p21Cip1/WAF1-associated CDK kinase activities. p21Cip1/WAF1 has been implicated in p53-mediated G1 arrest and apoptosis. In keratinocyte differentiation, Cip1/WAF1 induction is observed even in cells derived from p53-null mice. Similarly, keratinocyte differentiation is associated with induction of Cip1/WAF1 promoter activity in both wild-type and p53-negative keratinocytes. Induction of the Cip1/WAF1 promoter upon differentiation is abolished by expression of an adenovirus E1A oncoprotein (d1922/947), which is unable to bind p105-Rb, p107, or cyclin A but which still binds the nuclear phosphoprotein p300. Overexpression of p300 can suppress the E1A effect, independent of its direct binding to E1A. Thus, terminal differentiation-induced growth arrest in both keratinocyte and myoblast systems is associated with induction of Cip1/WAF1 expression. During keratinocyte differentiation, Cip1/WAF1 induction does not require p53 but depends on the transcriptional modulator p300.
Animals, Cell Differentiation/genetics, Cell Differentiation/physiology, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p21, Cyclins/genetics, Cyclins/physiology, E1A-Associated p300 Protein, Gene Expression Regulation, Genes, p53, Keratinocytes/cytology, Keratinocytes/metabolism, Mice, Mice, Inbred SENCAR, Muscles/cytology, Muscles/metabolism, Nuclear Proteins/physiology, Protein Kinase Inhibitors, Trans-Activators, Transcription Factors/physiology, Transcription, Genetic
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