Two posttranscriptional pathways that regulate p21(Cip1/Waf1/Sdi1) are identified by HPV16-E6 interaction and correlate with life span and cellular senescence

The p21((Cip1/Waf1/Sdi1)) protein is a cyclin-dependent kinase inhibitor th at is induced in normal human fibroblasts (NHF) following DNA damage, follo wing serum stimulation, and at cellular senescence. Expression of the human papilloma virus 16 E6 oncoprotein in NHF cells results in the loss of the p21 protein, independent of mRNA level under most conditions. The p21 prote in levels in NHF-E6 cells remained low following DNA damage or serum stimul ation even though mRNA levels increased. In contrast, the p21 protein was t ransiently induced in NHF-E6 cells at the onset of cellular senescence. Exp ression of the E6 oncoprotein in transformed cells had no effect on p21 pro tein levels. This demonstrates that two posttranscriptional pathways regula te expression of p21 protein in NHF cells under different conditions. Disru ption of posttranscriptional regulation is correlated with extension of lif e span, altered cell fate, and transformation.