Involvement of p21 and p27 in the regulation of CDK activity and cell cycle progression in the regenerating liver

Abstract

In tissue culture systems, p21 and p27 inhibit cyclindependent kinase (CDK) activity and cell cycle progression in response to numerous stimuli, but little is known about their involvement in cell growth in vivo. We examined the modulation of CDK activity by these proteins after 70% partial hepatectomy (PH), an in vivo model of synchronous hepatocyte cell cycle progression. After PH in BALB/c mice, p21 was induced during the prereplicative (G1) phase and was maximally expressed after peak hepatocyte DNA synthesis. p27 was present in quiescent liver and was minimally induced after PH. p21 and p27 immunoprecipitated with CDK2, CDK4, and cyclin D1 in the regenerating liver. The activity of CDK2-, CDK4-and cyclin D1-associated kinases was upregulated after PH, and maximal activity of these enzyme complexes corresponded to peak DNA synthesis. Immunodepletion experiments suggested that p27 plays a role in downregulating CDK2 activity before and after peak DNA synthesis. Compared to cogenic wild-type mice, p217/7 mice demonstrated evidence of markedly accelerated hepatocyte progression through G1 phase after PH: DNA synthesis, upregulation of cyclin A and PCNA, induction of cyclin D1-and CDK2-associated kinase activity, and appearance of a phosphorylated retinoblastoma protein (Rb) species occurred earlier in the p217/7 mice. These results suggest that p21 and p27 modulate CDK activity in the regenerating liver, and that p21 regulates the rate of progression through G1 phase of the cell cycle in vivo.

Hepatocyte expression and prognostic importance of senescence marker p21 in liver histopathology samples from dogs with chronic hepatitis

“…Although further studies are therefore required to further elucidate this relationship, the concept of cellular senescence warrants further consideration as replicative arrest affecting a large proportion of hepatocytes might significantly compromise the regenerative capacity of the liver in these cases. Furthermore, previous studies have suggested that p21 plays a key role in regulation of hepatocyte G1 phase progression and that transgenic mice with forced hepatic expression of p21 have markedly impaired regeneration after partial hepatectomy 29, 30…”

A20 protects mice from lethal radical hepatectomy by promoting hepatocyte proliferation via a p21waf1-dependent mechanism

“…36 DNA synthesis, cyclins/CDK activation and S phase gene expression occur earlier in transgenic p21 waf1 knockout mice than in wild type mice following partial hepatectomy. 37 In contrast, transgenic mice with hepatic overexpression of p21 waf1 demonstrate diminished liver size and markedly impaired hepatocyte proliferation following resection. 38 Little is known about the mechanisms regulating p21 waf1 expression in the liver.…”

Survivin initiates cell cycle entry by the competitive interaction with Cdk4/p16INK4a and Cdk2/Cyclin E complex activation

“…Another type of cell cycle suppressor, the WAF1/Kip1 family members, suppress Cyclin/Cdk complex activity. p21 WAF1 (Harper et al, 1993;Li et al, 1994) interacts with the Cyclin D/Cdk4 complex and the p27 Kip1 homolog (Polyak et al, 1994) suppresses the Cyclin E/Cdk2 complex (Sherr and Roberts, 1995;Reynisdottir and Massague, 1997;Albrecht et al, 1998). Thus, the cell cycle progression from G1 phase to S phase is initiated by phosphorylated Rb, which is regulated by Cyclin/Cdk complexes and multiple suppressor proteins.…”