ThePISSLREGene: Structure, Exon Skipping, and Exclusion as Tumor Suppressor in Breast Cancer

Crawford, Joanna; Ianzano, Leonarda; Savino, Maria; Whitmore, Scott A.; Cleton-Jansen, Anne Marie; Settasatian, Chatri; D’Apolito, Maria; Seshadri, Ram; Pronk, Jan C.; Auerbach, Arleen D.; Verlander, Peter C.; Mathew, Christopher G.; Tipping, Alex J.; Doggett, Norman A.; Zelante, Leopoldo; Callen, David F.; Savoia, Anna

doi:10.1006/geno.1998.5676

Cited by 40 publications

(32 citation statements)

References 25 publications

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“…P1 and P2, corresponding to putative kinases, were the first described (9, 10). Crawford et al recently described the genomic structure of CDK10, showing that P1 and P2 derive from the same gene by alternative splicing (11). Using 5Ј-RACE, they also obtained alternatively spliced 5Ј-end sequences corresponding to P1, P3, and P4 (but not P2).…”

Section: Discussionmentioning

confidence: 95%

Human CDK10 Gene Isoforms

Sergere

Thuret

et al. 2000

Biochemical and Biophysical Research Communications

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Section: Discussionmentioning

confidence: 95%

Human CDK10 Gene Isoforms

Sergere

Thuret

et al. 2000

Biochemical and Biophysical Research Communications

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“…CDK 10 is a cdc2-related kinase that contains the Tyr and Thr residues present in all protein kinases [Bagella et al, 2006]. Two isoforms of human CDK10 have been reported: hcdk10-1 and hcdk10-2 [Crawford et al, 1999]. Although little is known about the role of this protein, hcdk10-1 has been reported to bind to Ets2 transcription factor, thus modulating its transactivation activity [Kasten and Giordano, 2001].…”

Section: Discussionmentioning

confidence: 98%

Identification of nuclear structural protein alterations associated with seminomas

Leman

Magheli

Yong

et al. 2009

J of Cellular Biochemistry

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Currently, there are no specific markers available for the early detection and for monitoring testicular cancer. Based upon an approach that targets nuclear structure, we have identified a set of proteins that are specific for seminomas, which may then have clinical utility for the disease. Utilizing samples obtained from men with no evidence of testicular cancer (n = 5) as well as those with seminomas (n = 6), nuclear matrix proteins were extracted and separated using a high-resolution two-dimensional electrophoresis gel system. The proteins were identified by mass spectrometry analysis. These analyses revealed seven nuclear matrix proteins associated with the normal testes, which did not appear in the seminomas. In the seminomas, four nuclear matrix proteins were identified to be associated with the disease that were absent in the normal testes. Mass spectrometric and immunoblot analyses of these proteins revealed that one of the proteins identified in the normal testes appears to be StAR-related lipid transfer protein 7 (StARD7). In the non-seminoma tissues, one of the identified proteins appears to be cell division protein kinase 10 (CDK10). Both StarD7 and CDK10 could potentially be involved in cell differentiation and growth, and thus may serve as potential targets for therapy of prognostication of seminomas. This is the first study to examine the role of nuclear structural proteins as potential biomarkers in testicular cancer. We are currently examining the roles of some of the identified proteins as potential biomarkers for the disease.

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“…The fact that none of the shorter CDK10 isoforms interact robustly with cyclin M suggests that alternative splicing of the CDK10 gene (16,17) plays an important role in regulating CDK10 functions.…”

Section: Discussionmentioning

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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ThePISSLREGene: Structure, Exon Skipping, and Exclusion as Tumor Suppressor in Breast Cancer

Cited by 40 publications

References 25 publications

Human CDK10 Gene Isoforms

Human CDK10 Gene Isoforms

Identification of nuclear structural protein alterations associated with seminomas

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

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