Involvement ofthecell-cycle inhibitor Cipl/WAFJandthe ElA-associated p300protein interminal differentiation

ABSTRACT Themechanismofcell cyclewithdrawaldur-ing terminal differentiation is poorly understood. Wereporthere that the cyclin-dependent kinase (CDK) inhibitor p21ciPl/wAFl isinducedatearlytimesofbothkeratinocyteandmyoblast differentiation. p2jCiPl/WAF1 induction is accompa-nied by a drastic inhibition of total Cdk2, as well as p21CiPl/wAFl-associated CDKkinase activities. p21ciPl/wAFlhasbeenimplicatedinp53-mediated G, arrestandapoptosis.In keratinocyte differentiation, Cipi/WAFi induction is ob-served even in cells derived from p53-null mice. Similarly,keratinocyte differentiation is associated with induction of Cipi/WAFI promoter activity in both wild-type and p53-negativekeratinocytes.InductionoftheCipi/WAF)promoterupondifferentiation is abolished by expression of an adeno-virus EIAoncoprotein (dl922/947), whichis unable to bindp105-Rb, p107, or cyclin Abut which still binds the nuclearphosphoprotein p300. Overexpression of p300 can suppresstheElAeffect, independentofits directbindingtoE1A.Thus,terminal differentiation-induced growth arrest in both kera-tinocyte andmyoblastsystemsis associatedwithinduction of