Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control.
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.
Deng
C
C
Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Zhang
P
P
Harper
J W
JW
Elledge
S J
SJ
Leder
P
P
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001483:Base Sequence; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000502:physiology*; D004247:DNA / Q000235:genetics; D004249:DNA Damage; D016193:G1 Phase / Q000235:genetics / Q000502:physiology*; D016158:Genes, p53; D051379:Mice; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000235:genetics; D008941:Spindle Apparatus / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53; D004247:DNA