Cdk2ap1 Is Required for Epigenetic Silencing of Oct4 during Murine Embryonic Stem Cell Differentiation

Deshpande, Amit; Dai, Yujia; Kim, Yong; Kim, Jeffrey; Kimlin, Lauren; Gao, Kai; Wong, David T.

doi:10.1074/jbc.c800158200

Cited by 33 publications

(36 citation statements)

References 37 publications

(51 reference statements)

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“…1B). We have also demonstrated that the level of Oct3/4 was sustained in Cdk2ap1 Ϫ/Ϫ mESCs even under differentiation conditions (24). This result showed that the knock-out of the Cdk2ap1 gene in mESCs altered the differentiation program and maintains an undifferentiated phenotype even under differentiation stimulus.…”

Section: Altered Differentiation Competency In Cdk2ap1supporting

confidence: 50%

“…Deletion of Cdk2ap1 results in the mESCs becoming capable of self-renewing even in the absence of LIF signaling, with the phosphorylation of pRb at Ser 788 as one of the downstream events. This is in addition to other possible molecular alterations in the absence of Cdk2ap1 that could mediate the function of Cdk2ap1 in LIF-dependent mESC self-renewal/differentiation, such as the epigenetic control of Oct3/4 promoter, as demonstrated by our group (24).…”

Section: Discussionmentioning

confidence: 96%

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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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Section: Altered Differentiation Competency In Cdk2ap1supporting

confidence: 50%

Section: Discussionmentioning

confidence: 96%

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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“…These observations indicate that p12 CDK2AP1 acts as a growth suppressor through influencing mitosis, the S phase and the cell division cycle. A study has demonstrated that p12 CDK2AP1 is also important in promoting Oct4 promoter methylation during murine embryonic stem cell differentiation and thereby downregulates Oct4 expression levels (8). In addition, p12 CDK2AP1 has been shown to induce the epithelial-mesenchymal transition of hamster is associated with oral squamous cell carcinoma, breast cancer, esophageal squamous cell carcinoma, gastric cancer and colorectal cancer (10)(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Interaction between p12CDK2AP1 and a novel unnamed protein product inhibits cell proliferation by regulating the cell cycle

Liu

Yang

et al. 2013

Molecular Medicine Reports

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Abstract. Human p12CDK2AP1 protein is encoded by the cyclin-dependent kinase 2-associated protein 1 (CDK2AP1) gene. This protein suppresses cell growth, differentiation and angiogenesis in numerous types of carcinoma by interacting with certain cell cycle proteins, including CDK2 and DNA polymerase α/primase. p12 CDK2AP1 exerts its functions predominantly through protein-protein interactions. Therefore, the identification of other p12 CDK2AP1 -interacting proteins may clarify its role in cell cycle regulation and carcinogenesis. The aim of this study was to identify additional p12 CDK2AP1 -interacting proteins. A novel unnamed protein product (UPP, BC006130) was identified through using a yeast two-hybrid system. The interaction of p12 CDK2AP1 with the UPP was further verified by glutathione S-transferase pull-down and co-immunoprecipitation experiments in vitro. The qPCR results following overexpression and siRNA assays demonstrated that the expression levels of the UPP were mediated by the CDK2AP1 gene. Furthermore, overexpression of the UPP gene was shown to shorten the length of the G2/M phase of the cell cycle in normal and tumor cell lines in a flow cytometry assay. The results of human tumor xenografts experiments in Balb/c nude mice indicated that stable transfection with the UPP gene was able to inhibit tumor cell proliferation in vivo. Overall, this study identified and characterized a novel interactive protein of p12 CDK2AP1 , which may inhibit cell proliferation by mediating the cell cycle. It expands the understanding of the mechanisms of p12 CDK2AP1 and its potential as a cancer therapeutic target. IntroductionCyclin-dependent kinase 2-associated protein 1 (CDK2AP1) is a putative growth suppressor gene originally identified and isolated from normal keratinocytes (1). The human CDK2AP1 gene is 1.6 kb long and is located on chromosome 12q24.31 (2). The human and rodent polypeptides encoded by the CDK2AP1 gene share 97% identity, while the mouse and hamster sequences are identical (3). Human CDK2AP1 encodes a 115-amino acid peptide with a molecular mass of 12.4 kDa (pI 9.62), namely p12 CDK2AP1 (4). Previous studies have demonstrated that p12 CDK2AP1 negatively regulates cell growth by sequestering the monomeric non-phosphorylated form of CDK2 and targeting it for proteolysis to reduce the active pool of CDK2 in cells (5). The protein also reduces CDK2-mediated retinoblastoma protein phosphorylation by reversing the activity of TGF-β (6). A previous study has demonstrated that miR-21 downregulates p12 CDK2AP1 to stimulate cell proliferation and invasion (7). These observations indicate that p12 CDK2AP1 acts as a growth suppressor through influencing mitosis, the S phase and the cell division cycle. A study has demonstrated that p12 CDK2AP1 is also important in promoting Oct4 promoter methylation during murine embryonic stem cell differentiation and thereby downregulates Oct4 expression levels (8

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“…Recently, using a proteomic approach, CDK2AP1 has been identified to be a core subunit of NuRD (24). Moreover, the interaction of CDK2AP1 with MBD3 is required for epigenetic silencing of Oct4, which has been shown to be essential in the self-renewal of ESCs (22). Therefore, we hypothesized that Cdk2ap1 is required in the epigenetic regulation of ESCs, and deletion of Cdk2ap1 leads to changes in NuRD-dependent DNA methylation and corresponding gene expression.…”

mentioning

confidence: 99%

“…(21). Interestingly, Cdk2ap1 Ϫ/Ϫ mESCs fail to differentiate, and show Leukemia Inhibitory Factor (LIF)-independent self-renewal, remarkably similar to Mbd3-deficient mESCs (18,22,23). Recently, using a proteomic approach, CDK2AP1 has been identified to be a core subunit of NuRD (24).…”

mentioning

confidence: 99%

A Novel Regulatory Factor Recruits the Nucleosome Remodeling Complex to Wingless Integrated (Wnt) Signaling Gene Promoters in Mouse Embryonic Stem Cells

Kim¹,

Khalid²,

Vo³

et al. 2012

Journal of Biological Chemistry

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Cdk2ap1 Is Required for Epigenetic Silencing of Oct4 during Murine Embryonic Stem Cell Differentiation

Cited by 33 publications

References 37 publications

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

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

Interaction between p12CDK2AP1 and a novel unnamed protein product inhibits cell proliferation by regulating the cell cycle

A Novel Regulatory Factor Recruits the Nucleosome Remodeling Complex to Wingless Integrated (Wnt) Signaling Gene Promoters in Mouse Embryonic Stem Cells

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