p300 Alters Keratinocyte Cell Growth and Differentiation through Regulation of p21Waf1/CIP1

Abstract

P300 functions as a transcriptional co-activator to regulate many cellular responses such as cell growth, transformation, development and differentiation. It has been shown to affect the transcriptional activity of p53 which regulates p21^Waf1/CIP1 expression, however, the role of p300 in differentiation remains unclear. Knockdown of p300 protein with short hairpin RNA (shRNA) molecules delays human neonatal foreskin keratinocyte (HFKs) differentiation. Moreover, depletion of p300 increases the proliferative capacity of HFKs, extends the life span of cells and allows differentiated HFKs to re-enter the cell cycle. Studies indicate that depletion of p300 down-regulates the acetylation and expression of p53, and chromatin immunoprecipitation (ChIP) analysis shows that induction of p21^Waf1/CIP1 in early differentiation is a result of p300 dependent activation of p53 and that depletion of p21^Waf1/CIP1 results in the delay of differentiation and a phenotype similar to p300 depletion. p300 has a direct role in the control of cell growth and differentiation in primary epithelial cells, and p21^Waf1/CIP1 is an important mediator of these p300 functions.