Common and specific roles of the related CDK inhibitors p27 and p57 revealed by a knock-in mouse model

Although p27 and p57 are structurally related cyclin-dependent kinase inhibitors (CKIs), and are thought to perform similar functions, p27 knockout (p27 ^KO) and p57 ^KO mice show distinct phenotypes. Toelucidate theinvivo functionsofthese CKIs, wehave now generated a knock-in mouse model (p57 ^p27KI), in which the p57 gene has been replaced with the p27 gene. The p57 ^27KI mice are viable and appear healthy, with mostof the developmental defects characteristic ofp57 ^KOmice having been correctedbyp27 knock-in. Such developmental defects of p57 ^KO mice were also ameliorated in mice deficient in both p57 and the transcription factor E2F1, suggesting that loss of p57 promotes E2F1-dependent apoptosis. The developmental defects apparent in a few tissues of p57 ^KO mice were unaffected or only partially corrected by knock-in expression of p27. Thus, these observations indicate that p57 and p27 share many characteristics in vivo, but that p57 also performs specific functions not amenable to substitution with p27.