p12DOC-1, a growth suppressor, associates with DNA polymerase alpha/primase

MATSUO, K.

doi:10.1096/fj.14.10.1318

Cited by 40 publications

(30 citation statements)

References 7 publications

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“…CDK2AP1, a novel cell cycle regulator, has been shown to regulate cell cycle by interacting with CDK2 and preventing phosphorylation of pRB, thus rendering pRB active and able to regulate cell cycle [99]. CDK2AP1 has also been shown to interact with DNA polymerase-α/primase and reduce its activity [100]. This interaction affects the initiation, but not elongation step of DNA replication.…”

Section: Genetic Alteration In Preneoplastic Lesionsmentioning

confidence: 99%

Molecular mechanisms of head and neck cancer

Deshpande

Wong²

2008

Expert Review of Anticancer Therapy

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Background-With a global incidence rank of eight and a significant portion of head and neck malignancies (~90%), oral squamous cell carcinoma (OSCC) poses a major health risk and is one of the leading cause of mortality in developing nations [1]. Distribution of the incidence of OSCC varies across the world with south-central Asia and Africa leading, followed by eastern and central Europe, and to a lesser extent Australia, Japan, and the United States. Over the past few years there has been a drastic increase in the incidence of oral cancer in most parts of the world [2]. In the United States alone, with about 17 new cases/100,000, oral cancer is the fifth most common and sixth leading cause of cancer-related mortality per year [3].While men tend to have a higher incidence of OSCC (6.6/100,000) compared to women (2.9/100,000), there is an equal mortality rate between the sexes (50%).

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Section: Genetic Alteration In Preneoplastic Lesionsmentioning

confidence: 99%

Molecular mechanisms of head and neck cancer

Deshpande

Wong²

2008

Expert Review of Anticancer Therapy

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“…Murine Cdk2ap1 with only three amino acid deviations from the human CDK2AP1 is located at chromosome 5 (12,13). CDK2AP1 has been shown to be an S-phase regulator through two important cellular partners: CDK2 and DNA polymerase-␣/primase (14,15). Murine embryonic stem cells with disrupted expression of Cdk2ap1 showed an increased proliferation and an altered cell cycle profile with a reduced G 2 /M phase along with an increased CDK2 activity (13).…”

mentioning

confidence: 99%

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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“…Mechanistic studies have demonstrated that p12 CDK2AP1 binds to DNA polymerase α/primase protein, thereby inhibiting DNA replication (6). In addition, p12…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

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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p12DOC-1, a growth suppressor, associates with DNA polymerase alpha/primase

Cited by 40 publications

References 7 publications

Molecular mechanisms of head and neck cancer

Molecular mechanisms of head and neck cancer

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

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