Role of p12CDK2-AP1 in Transforming Growth Factor-β1-Mediated Growth Suppression

Hu, Miaofen G.; Hu, Guo‐fu; Kim, Yong; Tsuji, Takanori; McBride, Jim; Hinds, Philip W.; Wong, David T.

doi:10.1158/0008-5472.can-03-2284

Cited by 39 publications

(47 citation statements)

References 42 publications

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“…We have also found that p12 CDK2-AP1 mediates TGF-binduced growth inhibition (Hu et al, 2004). A recent report shows that p12 CDK2-AP1 expression levels are differentially downregulated in microsatellite-unstable colorectal cancer cell lines compared to microsatellitestable cell lines (Yuan et al, 2003).…”

Section: Introductionsupporting

confidence: 67%

p12CDK2-AP1 mediates DNA damage responses induced by cisplatin

et al. 2004

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We examined the biological role of p12 in cisplatin-mediated responses by using murine ES p12 CDK2-AP1 knockout clones generated by a targeted disruption of murine p12 . Homozygous knockout clones showed an increased cellular proliferation along with an increase in S and a decrease in G2/M phase populations. Interestingly, ES p12 CDK2-AP1 knockout clones showed a resistance to cisplatin treatment along with an increased DNA repair activity assessed by host cell reactivation assay using a cisplatin-damaged reporter DNA and a significant reduction of apoptosis upon cisplatin treatment. By using stable p12 CDK2-AP1 short interfering RNA (siRNA) clones from human normal oral keratinocytes, we confirmed that downregulation of p12 CDK2-AP1 resulted in a resistance to cisplatin. More interestingly, cisplatin treatment resulted in a reduction of CDK2 kinase activity in control clones, but p12 CDK2-AP1 knockout clones showed a sustained CDK2 kinase activity. These data suggest that p12 CDK2-AP1 plays a role in cisplatin-mediated cellular responses by modulating CDK2 activity. These data further suggest p12 CDK2-AP1 is a potential gene therapeutic agent for oral/head and neck cancer in conjunction with DNA-damaging agents such as cisplatin.

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Section: Introductionsupporting

confidence: 67%

p12CDK2-AP1 mediates DNA damage responses induced by cisplatin

et al. 2004

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“…To gain insight into the molecular and biochemical alterations resulting through Cdk2ap1 knock-out, we examined phenotypic and biochemical changes in vitro by using Cdk2ap1 Ϫ/Ϫ mESC clones. Based on the known effect of CDK2AP1 on CDK2 activity and pRb phosphorylation and previous findings on CDK2 activity and pRb phosphorylation in mESCs, we hypothesized that CDK2AP1 has a functional role in the differentiation competency of mESCs (15,23). As shown in Fig.…”

Section: Altered Differentiation Competency In Cdk2ap1mentioning

confidence: 85%

Cyclin-dependent Kinase 2-associating Protein 1 Commits Murine Embryonic Stem Cell Differentiation through Retinoblastoma Protein Regulation

Kim¹,

Deshpande²,

Dai³

et al. 2009

Journal of Biological Chemistry

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Mouse embryonic stem cells (mESCs) maintain pluripotency and indefinite self-renewal through yet to be defined molecular mechanisms. Leukemia inhibitory factor has been utilized to maintain the symmetrical self-renewal and pluripotency of mESCs in culture. It has been suggested that molecules with significant cellular effects on retinoblastoma protein (pRb) or its related pathways should have functional impact on mESC proliferation and differentiation. However, the involvement of pRb in pluripotent differentiation of mESCs has not been extensively elaborated. In this paper, we present novel experimental data indicating that Cdk2ap1 (cyclin-dependent kinase 2-associating protein 1), an inhibitor of G 1 /S transition through down-regulation of CDK2 and an essential gene for early embryonic development, confers competency for mESC differentiation. Targeted disruption of Cdk2ap1 in mESCs resulted in abrogation of leukemia inhibitory factor withdrawalinduced differentiation, along with altered pRb phosphorylation. The differentiation competency of the Cdk2ap1 ؊/؊ mESCs was restored upon the ectopic expression of Cdk2ap1 or a nonphosphorylatable pRb mutant (mouse Ser 788 3 Ala), suggesting that the CDK2AP1-mediated differentiation of mESCs was elicited through the regulation of pRb. Further analysis on mESC maintenance or differentiation-related gene expression supports the phosphorylation at serine 788 in pRb plays a significant role for the CDK2AP1-mediated differentiation of mESCs. These data clearly demonstrate that CDK2AP1 is a competency factor in the proper differentiation of mESCs by modulating the phosphorylation level of pRb. This sheds light on the role of the establishment of the proper somatic cell type cell cycle regulation for mESCs to enter into the differentiation process.

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“…1). TGF-β1 treatment of normal human keratinocytes increased cellular levels of CDK2AP1 mRNA and protein (Hu et al, 2004). Analysis of the data suggests that SMAD induced by TGF-β1 binds at the proximal promoter of the CDK2AP1 gene.…”

Section: Cdk2ap1 In Cancersmentioning

confidence: 94%

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et al. 2011

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Cancer research has been devoted toward an understanding of the molecular regulation and functional significance of cell-cycle regulators in the pathogenesis and development of cancers. Cyclin-dependent Kinase 2-associated Protein 1 (CDK2AP1) is one such cell-cycle regulator, originally identified as a growth suppressor and a prognostic marker for human oral/head and neck cancers. Functional importance and the molecular mechanism of CDK2AP1-mediated cell-cycle regulation have been documented over the years. Recent progress has shown that CDK2AP1 is a competency factor in embryonic stem cell differentiation. Deletion of CDK2AP1 leads to early embryonic lethality, potentially through altered differentiation capability of embryonic stem cells. More intriguingly, CDK2AP1 exerts its effect on stem cell maintenance/differentiation through epigenetic regulation. Cancer cells and stem cells share common cellular characteristics, most prominently in maintaining high proliferative potential through an unconventional cell-cycle regulatory mechanism. Cross-talk between cellular processes and molecular signaling pathways is frequent in any biological system. Currently, it remains largely elusive how cell-cycle regulation is mechanistically linked to epigenetic control. Understanding the molecular mechanism underlying CDK2AP1-mediated cell-cycle regulation and epigenetic control will set an example for establishing a novel and effective molecular link between these two important regulatory mechanisms.

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Role of p12CDK2-AP1 in Transforming Growth Factor-β1-Mediated Growth Suppression

Cited by 39 publications

References 42 publications

p12CDK2-AP1 mediates DNA damage responses induced by cisplatin

p12CDK2-AP1 mediates DNA damage responses induced by cisplatin

Cyclin-dependent Kinase 2-associating Protein 1 Commits Murine Embryonic Stem Cell Differentiation through Retinoblastoma Protein Regulation

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