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Up-regulation of p21(WAF1) by phorbol ester and calcium in human keratinocytes through a protein kinase C-dependent pathway

Lookup NU author(s): Carole Todd, Professor Nick ReynoldsORCiD


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Terminal differentiation in a variety of cell types has been associated with p53-independent up-regulation of p21(WAF1). p21(WAF1) mRNA and protein are expressed at low levels in normal human skin, but overexpression of p21(WAF1) has been observed in differentiating keratinocytes in involved psoriatic epidermis and in human squamous cell carcinoma. In this study we investigated by immunohistochemistry and Western blotting whether calcium and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate, well characterized differentiation signals, induce p21(WAF1) in cultured normal human keratinocytes and whether induction of p21(WAF1) in this system depends on protein kinase C activation or functional p53. Phorbol ester induced p21(WAF1) expression, which was maximal at 4 to 8 h with reduction back to baseline by 24 to 48 h. In contrast, increasing the extracellular Ca2+ concentration from 70 ╬╝mol/L to 1.5 mmol/L resulted in up-regulation of p21(WAF1) expression with a slower time course, with peak induction at 18 to 24 h. No parallel increase in p53 expression was observed in normal human keratinocytes. Up-regulation of p21(WAF1) was also observed in response to phorbol ester in HaCaT cells, which carry homozygous and inactivating mutations for p53. Induction of p21(WAF1) by phorbol ester and Ca2+ was inhibited by the specific protein kinase C inhibitor Ro 31-8220. The results demonstrate a differential time course of p21(WAF1) protein up-regulation in response to phorbol ester and Ca2+, signals that result in keratinocyte differentiation, and suggest that induction of p21(WAF1) in differentiating human keratinocytes occurs through protein kinase C-dependent and p53- independent mechanisms.

Publication metadata

Author(s): Todd C, Reynolds NJ

Publication type: Article

Publication status: Published

Journal: American Journal of Pathology

Year: 1998

Volume: 153

Issue: 1

Pages: 39-45

Print publication date: 01/07/1998

ISSN (print): 0002-9440

ISSN (electronic): 1525-2191

Publisher: American Society for Investigative Pathology

PubMed id: 9665463