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

Abstract

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. To elucidate the in vivo functions of these CKIs, we have now generated a knock-in mouse model (p57 p27KI ), in which the p57 gene has been replaced with the p27 gene. The p57 p27KI mice are viable and appear healthy, with most of the developmental defects characteristic of p57 KO mice having been corrected by p27 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.development ͉ cell cycle ͉ genetics

p57Kip2 and Cancer: Time for a Critical Appraisal

“…This finding supports the notion that differences between CDKN1B and CDKN1C knockout mice are due mostly to changes in the temporal and spatial expression of p27 Kip1 and p57 Kip2 proteins, and only in part to differences in their intrinsic molecular activities (93). However, some defects of CDKN1C knockout mice are not relieved in p27 Kip1 !p57 Kip2 knockin mice.…”

“…Although CDKN1B and CDKN1C knockout mice have distinct phenotypes, a knockin mouse model in which CDKN1C was replaced with CDKN1B showed a significant correction of most CDKN1C developmental defects (93). This finding supports the notion that differences between CDKN1B and CDKN1C knockout mice are due mostly to changes in the temporal and spatial expression of p27 Kip1 and p57 Kip2 proteins, and only in part to differences in their intrinsic molecular activities (93).…”

“…However, some defects of CDKN1C knockout mice are not relieved in p27 Kip1 !p57 Kip2 knockin mice. These include abnormalities of the renal papilla, placenta, and abdominal wall (93).…”

The function of p27KIP1during tumor development

“…This knock-in model has been generated to address the question of the tumor-prone phenotype with CDK inhibitory function. The knock-in mouse model shows an increase in spontaneous tumorigenesis in many tissues when compared with either wild-type or p27 KIP1 null animals (Kim et al, 2005;Susaki et al, 2009). However, many studies indicate that the function of p27 KIP1 cannot be solely attributed to its CDK inhibitory action.…”

A cross-talk between DNA methylation and H3 lysine 9 dimethylation at the KvDMR1 region controls the induction of Cdkn1c in muscle cells

“…4 The unique role of the Cdkn1c protein has been ascribed both to the presence of specific biochemical features of the protein, not shared by the other family members, 5,6 and to the specific expression pattern of the gene. 7 Cdkn1c is widely expressed in most tissues during embryogenesis but its expression drastically decreases at birth, becoming restricted to a subset of tissues and organs, such as heart, brain, lung, kidney, pancreas, skeletal muscle, testis, and placenta. 8 The levels of Cdkn1c protein are fine-tuned by multiple regulatory mechanisms, ranging from epigenetic to posttranslational control, in different cell types.…”