MICE LACKING P21(C/P1/WAF1) UNDERGO NORMAL DEVELOPMENT, BUT ARE DEFECTIVE IN G1 CHECKPOINT CONTROL

p21(CIP1/WAF1) is a CDK inhibitor regulated by the tumor suppressor p53 and is hypothesized to mediate G1 arrest. p53 has been suggested to derive anti-oncogenic properties from this relationship. To test these notions, we created mice lacking p21(CIP1/WAF1). They develop normally and (unlike p53(-/-) mice) have not developed spontaneous malignancies during 7 months of observation. Nonetheless, p21(-/-) embryonic fibroblasts are significantly deficient in their ability to arrest in G1 in response to DNA damage and nucleotide pool perturbation. p21(-/-) cells also exhibit a significant growth alteration in vitro, achieving a saturation density as high as that observed In p53(-/-) cells. In contrast, other aspects of p53 function, such as thymocytic apoptosis and the mitotic spindle checkpoint, appear normal. These results establish the role of p21(CIP1/WAF1) in the G1 checkpoint, but suggest that the anti-apoptotic and the anti-oncogenic effects of p53 are more complex.