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P21^WAF1 CONTROL OF EPITHELIAL CELL CYCLE AND CELL FATE

¹ Laboratory of Immunobiology, Division of Monoclonal Antibodies, Center for Biologics Evaluation and Research, FDA, NIH Bldg. 29B, Room 3NN04, HFM-564, Bethesda, MD 20892; and ² Department of Pathology and the Cardinal Bernardin Cancer Center, Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL 60153;

View larger version (22K): [in a new window]   Figure 1. Positive and negative regulation of G1 progression by p21WAF1. p21WAF1 exerts a negative effect on G1 progression by inhibiting the activity of cyclin E/cdk2 complexes which phosphorylate pRb in mid to late G1 (1), as well as the function of PCNA in S phase (4). However, p21WAF1 can facilitate G1 phase progression as an assembly factor for cyclin D/cdk4 complexes (2). The induction of D-type cyclins in early G1 recruits p21WAF1 into these active cyclin D/cdk4 or cyclin D/cdk6 complexes, depleting the free pool of p21WAF1, and relieving the inhibition on cyclin E/cdk2 (3).

View larger version (9K): [in a new window]   Figure 2. Stage-specific roles for p21WAF1 in epithelial carcinogenesis. p21WAF1 is involved in several normal cellular processes, including cell cycle progression, cell differentiation, and senescence. p21WAF1 also has an inhibitory effect on the initiation/promotion stage(s) of carcinogenesis, thereby reducing the formation of papillomas, but does not affect conversion of these benign tumors to carcinomas. Once a carcinoma is established, however, p21WAF1 helps maintain it in a well-differentiated state, thus impeding progression to spindle cell carcinomas.