Cdk10, a Cdc2-related kinase, associates with the Ets2 transcription factor and modulates its transactivation activity

Kasten, Margaret M.; Giordano, Antonio

doi:10.1038/sj.onc.1204295

Cited by 104 publications

(98 citation statements)

References 26 publications

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“…Cdk8 binds to CyclinC and Cdk9 binds to CyclinT, and they are also involved in the regulation of transcription (Malumbres and Barbacid 2005). No cyclin partner for Cdk10 has been identiWed so far; however, this kinase seems to be involved in regulating the G2-M phase by inhibition of Ets2 transactivation (Kasten and Giordano 2001). Cdk11 binds to CyclinL and is involved in mRNA splicing (Loyer et al 2008).…”

Section: Introductionmentioning

confidence: 99%

The CDK inhibitors in cancer research and therapy

Cicenas

Valius²

2011

J Cancer Res Clin Oncol

220

176

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Chemical compounds that interfere with an enzymatic function of kinases are useful for gaining insight into the complicated biochemical processes in mammalian cells. Cyclin-dependent kinases (CDK) play an essential role in the control of the cell cycle and/or proliferation. These kinases as well as their regulators are frequently deregulated in diVerent human tumors. Aberrations in CDK activity have also been observed in viral infections, Alzheimer's, Parkinson's diseases, ischemia and some proliferative disorders. This led to an intensive search for small-molecule CDK inhibitors not only for research purposes, but also for therapeutic applications. Here, we discuss seventeen CDK inhibitors and their use in cancer research or therapy. This review should help researchers to decide which inhibitor is best suited for the speciWc purpose of their research. For this purpose, the targets, commercial availability and IC 50 values are provided for each inhibitor. The review will also provide an overview of the clinical studies performed with some of these inhibitors.

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Section: Introductionmentioning

confidence: 99%

The CDK inhibitors in cancer research and therapy

Cicenas

Valius²

2011

J Cancer Res Clin Oncol

220

176

View full text Add to dashboard Cite

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“…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).…”

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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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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“…CDK10 is activated by cyclin M and interacts with ETS2. 6,7 To confirm the increase in ETS2 at the protein level, we performed western blots with lysates of subject-derived primary fibroblasts (see Figure 2D). The levels of ETS2 were substantially higher in CDK10 mutant cells than in control cells, which is in accordance with the finding that ETS2 is a substrate of the CDK10/cyclin M complex.…”

Section: Mice With Mutant Cdk10 Display Defects In Multiple Organsmentioning

confidence: 99%

“…4,5 CDK10 binds the transcription factor ETS2 and modulates its transactivation. 6 CDK10 kinase activity is regulated by the binding of CDK10 to cyclin M, which is the product of FAM58A (MIM: 300708). 7 CDK10/cyclin M complexes also have been shown to phosphorylate ETS2, leading directly to degradation of ETS2.…”

Section: Introductionmentioning

confidence: 99%

CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays

Windpassinger

Piard

Bonnard

et al. 2017

The American Journal of Human Genetics

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In five separate families, we identified nine individuals affected by a previously unidentified syndrome characterized by growth retardation, spine malformation, facial dysmorphisms, and developmental delays. Using homozygosity mapping, array CGH, and exome sequencing, we uncovered bi-allelic loss-of-function CDK10 mutations segregating with this disease. CDK10 is a protein kinase that partners with cyclin M to phosphorylate substrates such as ETS2 and PKN2 in order to modulate cellular growth. To validate and model the pathogenicity of these CDK10 germline mutations, we generated conditional-knockout mice. Homozygous Cdk10-knockout mice died postnatally with severe growth retardation, skeletal defects, and kidney and lung abnormalities, symptoms that partly resemble the disease's effect in humans. Fibroblasts derived from affected individuals and Cdk10-knockout mouse embryonic fibroblasts (MEFs) proliferated normally; however, Cdk10-knockout MEFs developed longer cilia. Comparative transcriptomic analysis of mutant and wild-type mouse organs revealed lipid metabolic changes consistent with growth impairment and altered ciliogenesis in the absence of CDK10. Our results document the CDK10 loss-of-function phenotype and point to a function for CDK10 in transducing signals received at the primary cilia to sustain embryonic and postnatal development.

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Cdk10, a Cdc2-related kinase, associates with the Ets2 transcription factor and modulates its transactivation activity

Cited by 104 publications

References 26 publications

The CDK inhibitors in cancer research and therapy

The CDK inhibitors in cancer research and therapy

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

CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays

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