Involvement of the cell-cycle inhibitor Cip1/WAF1 and the E1A-associated p300 protein in terminal differentiation.
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.
Missero
C
C
Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown 02129, USA.
Calautti
E
E
Eckner
R
R
Chin
J
J
Tsai
L H
LH
Livingston
D M
DM
Dotto
G P
GP
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000502:physiology*; D050881:E1A-Associated p300 Protein; D005786:Gene Expression Regulation; D016158:Genes, p53; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018632:Mice, Inbred SENCAR; D009132:Muscles / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000502:physiology*; D047428:Protein Kinase Inhibitors; D015534:Trans-Activators; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D015534:Trans-Activators; D014157:Transcription Factors; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse