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PMID: 7777529 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

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 ·Vol. 92 ·No. 12 ·1995-06-06 ·Pages 5451-5

Missero C, Calautti E, Eckner R, Chin J, Tsai LH, Livingston DM, Dotto GP

Abstract

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.

Related Genes
Cip1 WAF1 p53
MeSH Terms
Animals Cell Differentiation/genetics,physiology Cells, Cultured Cyclin-Dependent Kinase Inhibitor p21 Cyclins/genetics,physiology E1A-Associated p300 Protein Gene Expression Regulation Genes, p53 Keratinocytes/cytology,metabolism Mice Mice, Inbred SENCAR Muscles/cytology,metabolism Nuclear Proteins/physiology Protein Kinase Inhibitors Trans-Activators Transcription Factors/physiology Transcription, Genetic
Chemicals
Cdkn1a protein, mouse Cyclin-Dependent Kinase Inhibitor p21 Cyclins Nuclear Proteins Protein Kinase Inhibitors Trans-Activators Transcription Factors E1A-Associated p300 Protein Ep300 protein, mouse
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Missero C
Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown 02129, USA.
Calautti E
Eckner R
Chin J
Tsai L H
Livingston D M
Dotto G P
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.92.12.5451
Published
1995-06-06
Pages
5451-5
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC41712
Subset
IM
Grants
NIAMS NIH HHS · AR39190 · United States
NCI NIH HHS · CA16038 · United States
External Links
PubMed source DOI: 10.1073/pnas.92.12.5451 PMC Full Text View journal details
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