p27Kip1 Stabilization Is Essential for the Maintenance of Cell Cycle Arrest in Response to DNA Damage

Cuadrado, Myriam; Gutierrez-Martinez, Paula; Swat, Aneta; Nebreda, Ángel R.; Fernández-Capetillo, Óscar

doi:10.1158/0008-5472.can-09-0729

Cited by 60 publications

(61 citation statements)

References 30 publications

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“…Hence, repression of the CDKs by miR-182-5p would lead to activation of RB and a cell cycle arrest, enabling efficient DNA repair. The second class is the components of the SCF complex that are responsible for the ubiquitylation of several proteins that are essential for the DDR, e.g., SKP1 and 2, components of the SCF complex, which are known to degrade p27 KIP1 (CDKN1B), an essential mediator of cell cycle arrest in response to DNA damage (Cuadrado et al 2009). Another component of the SCF complex, BTRC, is also known to ubiquitylate ATF4, which plays a role in maintaining genomic integrity (Lassot et al 2001).…”

Section: Resultsmentioning

confidence: 99%

MicroRNA-182-5p targets a network of genes involved in DNA repair

Krishnan

Steptoe

Martin

et al. 2012

RNA

114

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MicroRNAs are noncoding regulators of gene expression, which act by repressing protein translation and/or degrading mRNA. Many have been shown to drive tumorigenesis in cancer, but functional studies to understand their mode of action are typically limited to single-target genes. In this study, we use synthetic biotinylated miRNA to pull down endogenous targets of miR-182-5p. We identified more than 1000 genes as potential targets of miR-182-5p, most of which have a known function in pathways underlying tumor biology. Specifically, functional enrichment analysis identified components of both the DNA damage response pathway and cell cycle to be highly represented in this target cohort. Experimental validation confirmed that miR-182-5p-mediated disruption of the homologous recombination (HR) pathway is a consequence of its ability to target multiple components in that pathway. Although there is a strong enrichment for the cell cycle ontology, we do not see primary proliferative defects as a consequence of miR-182-5p overexpression. We highlight targets that could be responsible for miR-182-5p-mediated disruption of other biological processes attributed in the literature so far. Finally, we show that miR-182-5p is highly expressed in a panel of human breast cancer samples, highlighting its role as a potential oncomir in breast cancer.

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Section: Resultsmentioning

confidence: 99%

MicroRNA-182-5p targets a network of genes involved in DNA repair

Krishnan

Steptoe

Martin

et al. 2012

RNA

114

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“…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).…”

Section: Introductionmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

p27Kip1 controls cytokinesis via the regulation of citron kinase activation

Serres

Kossatz-Boehlert²,

Chi³

et al. 2012

J. Clin. Invest.

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p27 Kip1 (p27) acts as a tumor suppressor by inhibiting cyclin-cyclin-dependent kinase (cyclin-CDK) activity. However, mice expressing a form of p27 that is unable to bind or inhibit cyclin-CDK complexes (p27 CK-) have increased incidence of tumor development as compared with wild-type and p27 -/-mice, revealing an oncogenic role for p27. Here, we identified a phenotype of multinucleation and polyploidy in p27 CK-mice not present in p27 -/-animals, suggesting a role for p27 in G 2 /M that is independent of cyclin-CDK regulation. Further analysis revealed that p27 CK-expression caused a cytokinesis and abscission defect in mouse embryonic fibroblasts. We identified the Rho effector citron kinase (citron-K) as a p27-interacting protein in vitro and in vivo and found that p27 and citron-K colocalized at the contractile ring and mid-body during telophase and cytokinesis. Moreover, overexpression of the minimal p27-binding domain of citron-K was sufficient to rescue the phenotype caused by p27 CK-. Conversely, expression of a mutant p27 CK-unable to bind citron-K did not induce multinucleation. Finally, by binding to citron-K, p27 prevented the interaction of citron-K with its activator RhoA. Taken together, these data suggest a role for p27 during cytokinesis via the regulation of citron-K activity.

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“…Some reports suggest that the induction of p27/kip1 by DNA damage is unaltered (Vikhanskaya et al, 1996;Balasubramanian et al, 1999;Vivo et al, 2003), but others have observed increases in p27/kip1 increment (Zhou et al, 2004;He et al, 2006;Cuadrado et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

von Hippel–Lindau protein promotes Skp2 destabilization on DNA damage

et al. 2011

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Germline mutations in the von Hippel-Lindau (VHL) tumor suppressor gene cause VHL disease, a rare and autosomaldominant genetic syndrome. Because VHL protein (pVHL) is the master regulator of hypoxia-inducible factor alpha (HIFa), the most prominent feature of VHL disease is the deregulation of HIFa proteins. However, the precise mechanism by which the loss of pVHL function contributes to tumorigenesis is not fully understood. Here, we show that pVHL destabilizes the F-box protein Skp2, a chief component of Skp, Cullin, F-box-containing complex that promotes DNA synthesis in the S phase. The b-domain of pVHL interacts with Skp2, stimulating proteasome-dependent Skp2 degradation, but the destabilization of Skp2 does not depend on the E3 ubiquitin ligase activity of pVHL. Notably, the generation of DNA damage induces Skp2 degradation, which is attenuated by the suppression of endogenous pVHL expression. One possible mechanism of pVHL-dependent Skp2 degradation entails the antagonizing of Akt-mediated Skp2 phosphorylation, which maintains Skp2 stability. Reintroduction of VHL into VHL-null renal cell carcinoma (RCC) cells decreased Skp2 levels and restored DNA damage-dependent Skp2 degradation. These results identify the tumor suppressor function of pVHL in delaying the S-phase progression to inhibit cell proliferation on DNA damage. Clinically, this report explains as to why Skp2 accumulates abnormally in RCC tissues.

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p27Kip1 Stabilization Is Essential for the Maintenance of Cell Cycle Arrest in Response to DNA Damage

Cited by 60 publications

References 30 publications

MicroRNA-182-5p targets a network of genes involved in DNA repair

MicroRNA-182-5p targets a network of genes involved in DNA repair

p27Kip1 controls cytokinesis via the regulation of citron kinase activation

von Hippel–Lindau protein promotes Skp2 destabilization on DNA damage

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