In normal epithelia differentiation and proliferation are regulated by factors involving p53 and related pathways. WAF1/CIP1 protein is believed to inhibit cell growth as a downstream mediator of p53 function. Also, WAF1/CIP1 is identified as a candidate gene linking differentiation signals to G1 arrest. Different epithelia with different keratinizing profiles respond differently to differentiation/proliferation signals, such as calcium or interferon gamma (IFNgamma). Other factors, such as p53 mutation or presence of human papillomaviruses (HPVs) also affect responses to those signals. Since WAF1/CIP1 can be regulated via a p53-dependent or an independent manner, our study aimed to determine: a.) differentiation-related expression of WAF1/CIP1 in keratinocytes, b.) involvement of WAF1/CIP1 in IFNgamma action, and c.) p53-dependence of WAF1/CIP1 transcription under these conditions. The results demonstrated that differentiation increases WAF1/CIP1 transcription in keratinizing but not in nonkeratinizing keratinocytes in a p53-independent manner. IFNgamma upregulated WAF1/CIP1 in keratinizing keratinocytes in a differentiation and p53 dependent manner. Inactivation of wild type p53 by mutation or by presence of HPVs uncouples IFNgamma-mediated WAF1/CIP1 transcription from p53 and from differentiation. Our data suggest a mechanism which operates via WAF1/CIP1 in keratinocytes and regulates epithelial differentiation/proliferation under different physiological conditions.