Phosphorylation of CDK2 at threonine 160 regulates meiotic pachytene and diplotene progression in mice

Liu, Wenjing; Wang, Lu; Zhao, Weidong; Song, Gendi; Xu, Rener; Wang, Guishuan; Wang, Fei; Li, Wenqing; Lian, Jie; Tian, Hui; Wang, Xiaorong; Sun, Fei

doi:10.1016/j.ydbio.2014.04.018

Cited by 20 publications

(18 citation statements)

References 37 publications

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“…The pro-apoptotic roles of both CDK2 isoforms in our study were supported by previous findings that the p39 isoform, produced through alternative splicing, exhibited similar cellular functions as p33 CDK2, albeit with ϳ50% lower activity (30). Recent evidence suggests that the two CDK2 isoforms differ in their binding partners and expression patterns (31). Indeed, DOX treatment induced a transient increase in p33 and prolonged expression of p39 in cardiomyocytes.…”

Section: Discussionsupporting

confidence: 88%

Inhibition of cyclin-dependent kinase 2 protects against doxorubicin-induced cardiomyocyte apoptosis and cardiomyopathy

Xia

Liu

Chen

et al. 2018

Journal of Biological Chemistry

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Edited by Xiao-Fan WangWith the rapid increase in cancer survival because of improved diagnosis and therapy in the past decades, cancer treatment-related cardiotoxicity is becoming an urgent healthcare concern. The anthracycline doxorubicin (DOX), one of the most effective chemotherapeutic agents to date, causes cardiomyopathy by inducing cardiomyocyte apoptosis. We demonstrated previously that overexpression of the cyclin-dependent kinase (CDK) inhibitor p21 promotes resistance against DOXinduced cardiomyocyte apoptosis. Here we show that DOX exposure provokes cardiac CDK2 activation and cardiomyocyte cell cycle S phase reentry, resulting in enhanced cellular sensitivity to DOX. Genetic or pharmacological inhibition of CDK2 markedly suppressed DOX-induced cardiomyocyte apoptosis. Conversely, CDK2 overexpression augmented DOX-induced apoptosis. We also found that DOX-induced CDK2 activation in the mouse heart is associated with up-regulation of the pro-apoptotic BCL2 family member BCL2-like 11 (Bim), a BH3-only protein essential for triggering Bax/Bak-dependent mitochondrial outer membrane permeabilization. Further experiments revealed that DOX induces cardiomyocyte apoptosis through CDK2-dependent expression of Bim. Inhibition of CDK2 with roscovitine robustly repressed DOX-induced mitochondrial depolarization. In a cardiotoxicity model of chronic DOX exposure (5 mg/kg weekly for 4 weeks), roscovitine administration significantly attenuated DOX-induced contractile dysfunction and ventricular remodeling. These findings identify CDK2 as a key determinant of DOX-induced cardiotoxicity. CDK2 activation is necessary for DOX-induced Bim expression and mitochondrial damage. Our results suggest that pharmacological inhibition of CDK2 may be a cardioprotective strategy for preventing anthracycline-induced heart damage.

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Section: Discussionsupporting

confidence: 88%

Inhibition of cyclin-dependent kinase 2 protects against doxorubicin-induced cardiomyocyte apoptosis and cardiomyopathy

Xia

Liu

Chen

et al. 2018

Journal of Biological Chemistry

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“…14), suggesting a specific interaction with CDK2. Among the 33-kDa and the 39-kDa isoforms of CDK2, CNTD1 preferentially interacted with the 39-kDa isoform, which has been implicated in meiosis-specific CDK2 functions previously [40][41][42] . Further, the CDK2-CNTD1 interaction did not require catalytic activity of CDK2 (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Proline-rich protein PRR19 functions with cyclin-like CNTD1 to promote meiotic crossing over in mouse

et al. 2020

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Orderly chromosome segregation is enabled by crossovers between homologous chromosomes in the first meiotic division. Crossovers arise from recombination-mediated repair of programmed DNA double-strand breaks (DSBs). Multiple DSBs initiate recombination, and most are repaired without crossover formation, although one or more generate crossovers on each chromosome. Although the underlying mechanisms are ill-defined, the differentiation and maturation of crossover-specific recombination intermediates requires the cyclin-like CNTD1. Here, we identify PRR19 as a partner of CNTD1. We find that, like CNTD1, PRR19 is required for timely DSB repair and the formation of crossover-specific recombination complexes. PRR19 and CNTD1 co-localise at crossover sites, physically interact, and are interdependent for accumulation, indicating a PRR19-CNTD1 partnership in crossing over. Further, we show that CNTD1 interacts with a cyclin-dependent kinase, CDK2, which also accumulates in crossover-specific recombination complexes. Thus, the PRR19-CNTD1 complex may enable crossover differentiation by regulating CDK2.

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“…The ability of endogenous Cdk2 to bind to Sun1 (ref. 49 ) and of recombinant Cdk2-RingoA to phosphorylate the N-terminus of Sun1, suggests a phosphorylation-dependent mechanism. It should be noted that although loss of Sun1 might explain several features of the RingoA-deficient spermatocytes, it is unlikely to explain the telomere fusion phenotype.…”

Section: Discussionmentioning

confidence: 98%

Essential role of the Cdk2 activator RingoA in meiotic telomere tethering to the nuclear envelope

et al. 2016

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Cyclin-dependent kinases (CDKs) play key roles in cell cycle regulation. Genetic analysis in mice has revealed an essential role for Cdk2 in meiosis, which renders Cdk2 knockout (KO) mice sterile. Here we show that mice deficient in RingoA, an atypical activator of Cdk1 and Cdk2 that has no amino acid sequence homology to cyclins, are sterile and display meiotic defects virtually identical to those observed in Cdk2 KO mice including non-homologous chromosome pairing, unrepaired double-strand breaks, undetectable sex-body and pachytene arrest. Interestingly, RingoA is required for Cdk2 targeting to telomeres and RingoA KO spermatocytes display severely affected telomere tethering as well as impaired distribution of Sun1, a protein essential for the attachment of telomeres to the nuclear envelope. Our results identify RingoA as an important activator of Cdk2 at meiotic telomeres, and provide genetic evidence for a physiological function of mammalian Cdk2 that is not dependent on cyclins.

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Phosphorylation of CDK2 at threonine 160 regulates meiotic pachytene and diplotene progression in mice

Cited by 20 publications

References 37 publications

Inhibition of cyclin-dependent kinase 2 protects against doxorubicin-induced cardiomyocyte apoptosis and cardiomyopathy

Inhibition of cyclin-dependent kinase 2 protects against doxorubicin-induced cardiomyocyte apoptosis and cardiomyopathy

Proline-rich protein PRR19 functions with cyclin-like CNTD1 to promote meiotic crossing over in mouse

Essential role of the Cdk2 activator RingoA in meiotic telomere tethering to the nuclear envelope

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