p27^kip1 Deficiency Impairs G₂/M Arrest in Response to DNA Damage, Leading to an Increase in Genetic Instability

Abstract

p27kip1 is a cyclin-dependent kinase inhibitor and a tumor suppressor. In some tumors, p27 suppresses tumor growth by inhibition of cell proliferation. However, this is not universally observed, implying additional mechanisms of tumor suppression by p27. p27-deficient mice are particularly susceptibility to genotoxininduced tumors, suggesting a role for p27 in the DNA damage response. To test this hypothesis, we measured genotoxin-induced mutations and chromosome damage in p27-deficient mice. Both p27 ؉/؊ and p27 ؊/؊ mice displayed a higher N-ethyl-N-nitrosourea-induced mutation frequency in the colon than p27 ؉/؉ littermates. Furthermore, cells from irradiated p27-deficient mice exhibited a higher number of chromatid breaks and showed modestly increased micronucleus formation compared to cells from wild-type littermates. To determine if this mutator phenotype was related to the cell cycle-inhibitory function of p27, we measured cell cycle arrest in response to DNA damage. Both normal and tumor cells from p27-deficient mice showed impaired G 2 /M arrest following low doses of ionizing radiation. Thus, p27 may inhibit tumor development through two mechanisms. The first is by reducing the proliferation of cells that have already sustained an oncogenic lesion. The second is by transient inhibition of cell cycle progression following genotoxic insult, thereby minimizing chromosome damage and fixation of mutations.

Cyclin E2 induces genomic instability by mechanisms distinct from cyclin E1

“…The pocket protein p107, along with p21 Waf1/Cip1 and p27 Kip1 , can restrain CDK2/CDK1-induced genomic instability during cell cycle exit, 29,36 and overexpression of cyclin E1-CDK2 can prevent nuclear translocation of repressor complexes containing p107 and p130. 37 Here we found that cyclin E1 overexpression also coincided with increased expression of p107, likely leading to negative feedback on cyclin E1-CDK2 activity.…”

A bioinformatical and functional approach to identify novel strategies for chemoprevention of colorectal cancer

“…The pathways that were specifically enriched in adenomas in our analysis are known to be activated in colorectal carcinogenesis (causal, resulting or compensatory) such as the Wnt pathway (Midgley and Kerr, 1999), cell cycle routes (Hao et al, 1998), DNA base metabolism, transcription, ATM (Kwong et al, 2008;Paulson et al, 2008), ARF, p27 (Payne et al, 2008) and p53 (Einspahr et al, 2006) signaling routes. In addition, we found novel pathways unique to adenomas, among which are the Rb pathway, the Src pathway, folate biosynthesis and the PTC1 pathway.…”

p27Kip1 controls cytokinesis via the regulation of citron kinase activation

“…These phenotypes are completely rescued in double Skp2 -/-p27 -/-mice, indicating that the accumulation of p27 in S, G 2 , and M phases in Skp2 -/-cells is responsible for a failure to progress to mitosis, resulting in polyploidy (20,21). Recently, several groups reported that ionizing radiation or DNAdamaging drugs could induce p27 expression to trigger an arrest in G 2 /M and that in the absence of p27, cells failed to undergo cell cycle arrest (22)(23)(24). Moreover, the loss of p27 was associated with increased chromosomal instability in response to DNA damage, as cells could proceed through mitosis with unrepaired DNA (22)(23)(24).…”

“…Recently, several groups reported that ionizing radiation or DNAdamaging drugs could induce p27 expression to trigger an arrest in G 2 /M and that in the absence of p27, cells failed to undergo cell cycle arrest (22)(23)(24). Moreover, the loss of p27 was associated with increased chromosomal instability in response to DNA damage, as cells could proceed through mitosis with unrepaired DNA (22)(23)(24). In addition, p27 deficiency impeded Rad51-mediated DNA repair due to increased CDK1-mediated phosphorylation of BRCA2, which inhibits the BRCA2-Rad51 interaction and Rad51-mediated repair (22).…”