Deng C, Zhang P, Harper J W, Elledge S J, Leder P
Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Cell. 1995 Aug 25;82(4):675-84. doi: 10.1016/0092-8674(95)90039-x.
p21CIP1/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 p21CIP1/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 p21CIP1/WAF1 in the G1 checkpoint, but suggest that the anti-apoptotic and the anti-oncogenic effects of p53 are more complex.
p21CIP1/WAF1是一种由肿瘤抑制因子p53调控的细胞周期蛋白依赖性激酶（CDK）抑制剂，据推测它可介导G1期阻滞。有人认为p53正是通过这种关系获得了抗癌特性。为了验证这些观点，我们培育出了缺乏p21CIP1/WAF1的小鼠。这些小鼠发育正常，并且（与p53基因敲除小鼠不同）在7个月的观察期内未发生自发性恶性肿瘤。然而，p21基因敲除的胚胎成纤维细胞在响应DNA损伤和核苷酸库扰动时，其在G1期阻滞的能力显著不足。p21基因敲除的细胞在体外也表现出显著的生长变化，达到了与p53基因敲除细胞中观察到的一样高的饱和密度。相比之下，p53功能的其他方面，如胸腺细胞凋亡和有丝分裂纺锤体检查点，看起来是正常的。这些结果确立了p21CIP1/WAF1在G1期检查点中的作用，但表明p53的抗凋亡和抗癌作用更为复杂。
