CDK10 functions as a tumor suppressor gene and regulates survivability of biliary tract cancer cells

Yu, Jianhua; Zhong, Xian; Zhang, Weiguang; Wang, Zhidong; Dong, Qian; Tai, Sheng; Li, Hui; Cui, Yunfu

doi:10.3892/or.2011.1617

Cited by 37 publications

(59 citation statements)

References 22 publications

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“…Finally, our findings will facilitate the general exploration of the biological functions of CDK10 and, in particular, its role in the control of cell division. Previous studies have suggested either a positive role in cell cycle control (5, 6) or a tumor-suppressive activity in some cancers (7,8). The severe growth retardation exhibited by STAR patients strongly suggests that CDK10/cyclin M plays an important role in the control of cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…This knowledge gap has largely impeded the exploration of its biological functions. CDK10 can act as a positive cell cycle regulator in some cells (5, 6) or as a tumor suppressor in others (7,8). CDK10 interacts with the ETS2 (v-ets erythroblastosis virus E26 oncogene homolog 2) transcription factor and inhibits its transcriptional activity through an unknown mechanism (9).…”

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confidence: 99%

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CDK10/cyclin M is a protein kinase that controls ETS2 degradation and is deficient in STAR syndrome

Guen

Gamble

Flajolet

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

104

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Cyclin-dependent kinases (CDKs) regulate a variety of fundamental cellular processes. CDK10 stands out as one of the last orphan CDKs for which no activating cyclin has been identified and no kinase activity revealed. Previous work has shown that CDK10 silencing increases ETS2 (v-ets erythroblastosis virus E26 oncogene homolog 2)-driven activation of the MAPK pathway, which confers tamoxifen resistance to breast cancer cells. The precise mechanisms by which CDK10 modulates ETS2 activity, and more generally the functions of CDK10, remain elusive. Here we demonstrate that CDK10 is a cyclin-dependent kinase by identifying cyclin M as an activating cyclin. Cyclin M, an orphan cyclin, is the product of FAM58A, whose mutations cause STAR syndrome, a human developmental anomaly whose features include toe syndactyly, telecanthus, and anogenital and renal malformations. We show that STAR syndrome-associated cyclin M mutants are unable to interact with CDK10. Cyclin M silencing phenocopies CDK10 silencing in increasing c-Raf and in conferring tamoxifen resistance to breast cancer cells. CDK10/cyclin M phosphorylates ETS2 in vitro, and in cells it positively controls ETS2 degradation by the proteasome. ETS2 protein levels are increased in cells derived from a STAR patient, and this increase is attributable to decreased cyclin M levels. Altogether, our results reveal an additional regulatory mechanism for ETS2, which plays key roles in cancer and development. They also shed light on the molecular mechanisms underlying STAR syndrome.C yclin-dependent kinases (CDKs) play a pivotal role in the control of a number of fundamental cellular processes (1). The human genome contains 21 genes encoding proteins that can be considered as members of the CDK family owing to their sequence similarity with bona fide CDKs, those known to be activated by cyclins (2). Although discovered almost 20 y ago (3, 4), CDK10 remains one of the two CDKs without an identified cyclin partner. This knowledge gap has largely impeded the exploration of its biological functions. CDK10 can act as a positive cell cycle regulator in some cells (5, 6) or as a tumor suppressor in others (7,8). CDK10 interacts with the ETS2 (v-ets erythroblastosis virus E26 oncogene homolog 2) transcription factor and inhibits its transcriptional activity through an unknown mechanism (9). CDK10 knockdown derepresses ETS2, which increases the expression of the c-Raf protein kinase, activates the MAPK pathway, and induces resistance of MCF7 cells to tamoxifen (6).Here, we deorphanize CDK10 by identifying cyclin M, the product of FAM58A, as a binding partner. Mutations in this gene that predict absence or truncation of cyclin M are associated with STAR syndrome, whose features include toe syndactyly, telecanthus, and anogenital and renal malformations in heterozygous females (10). However, both the functions of cyclin M and the pathogenesis of STAR syndrome remain unknown. We show that a recombinant CDK10/cyclin M heterodimer is an active protein kinase that phosphorylates ETS2 in v...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

CDK10/cyclin M is a protein kinase that controls ETS2 degradation and is deficient in STAR syndrome

Guen

Gamble

Flajolet

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

104

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“…The authors proceeded to highlight the clinical relevance of this finding by demonstrating that breast cancer patients with ERα-positive tumors that express low levels of CDK10 (owing to methylation and silencing of the CDK10 promoter) display higher occurrence of relapse and poorer overall survival. Together with data from other groups (Leman et al, 2009;Yu et al, 2012;Zhong et al, 2012), there is now compelling evidence to suggest that Cdk10 might function as a tumor suppressor in normal cells by inhibiting the oncogenic potential of its interacting partner Ets2. Whether Cdk10 has other physiological roles in addition to the suppression of Ets2 transactivation activity remains to be determined.…”

Section: Kinase-independent Transcriptional Functionsmentioning

confidence: 93%

Cdks, cyclins and CKIs: roles beyond cell cycle regulation

2013

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SummaryCyclin-dependent kinases (Cdks) are serine/threonine kinases and their catalytic activities are modulated by interactions with cyclins and Cdk inhibitors (CKIs). Close cooperation between this trio is necessary for ensuring orderly progression through the cell cycle. In addition to their well-established function in cell cycle control, it is becoming increasingly apparent that mammalian Cdks, cyclins and CKIs play indispensable roles in processes such as transcription, epigenetic regulation, metabolism, stem cell self-renewal, neuronal functions and spermatogenesis. Even more remarkably, they can accomplish some of these tasks individually, without the need for Cdk/cyclin complex formation or kinase activity. In this Review, we discuss the latest revelations about Cdks, cyclins and CKIs with the goal of showcasing their functional diversity beyond cell cycle regulation and their impact on development and disease in mammals.

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“…Overexpression of human CDK10 inhibits the proliferation of human biliary tract cancer (29) and hepatocellular carcinoma (30). By contrast, zebrafish cdk10 is not involved in G 2 /M phase progression.…”

Section: Discussionmentioning

confidence: 97%

“…Recent studies suggested that human CDK10 functions as a tumor suppressor gene, preventing cell proliferation in breast cancer (12), biliary tract cancer cells (29), and hepatoma (30). However, the developmental function of CDK10 remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of Cyclin-dependent Kinase 10 (cdk10) Gene Impairs Neural Progenitor Survival via Modulation of raf1a Gene Expression

Yeh

Kao

Cheng

et al. 2013

Journal of Biological Chemistry

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Background: CDK10 is involved in cell proliferation; however, the function of CDK10 in cell development remains unclear. Results: The knockdown of cdk10 results in the apoptosis of neural progenitor cells (NPCs) through enhanced raf1a expression. Conclusion: Zebrafish cdk10 exhibits an important function in neurogenesis by the modulation of the raf1a level during development. Significance: These findings emphasize the significance of cdk10 in NPC survival.

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CDK10 functions as a tumor suppressor gene and regulates survivability of biliary tract cancer cells

Cited by 37 publications

References 22 publications

CDK10/cyclin M is a protein kinase that controls ETS2 degradation and is deficient in STAR syndrome

CDK10/cyclin M is a protein kinase that controls ETS2 degradation and is deficient in STAR syndrome

Cdks, cyclins and CKIs: roles beyond cell cycle regulation

Knockdown of Cyclin-dependent Kinase 10 (cdk10) Gene Impairs Neural Progenitor Survival via Modulation of raf1a Gene Expression

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