p12CDK2-AP1 mediates DNA damage responses induced by cisplatin

Kim, Yong; McBride, Jim; Zhang, Rong; Zhou, Xiaofeng; Wong, David T.

doi:10.1038/sj.onc.1208222

Cited by 16 publications

(27 citation statements)

References 55 publications

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“…The present study focused on testing the hypothesis that the putative tumor suppressor and cell cycle regulator p12 could also act as an inhibitor of tumor cell growth in vivo. p12 has been shown to induce cell cycle arrest, growth suppression, repression of DNA replication, and apoptosis in vitro (18,20,38,39), and also to regulate cell growth by association with CDK2, DNA polymerase a/primase, and p14 DOC1R (15,16,40). The present study supports previous in vitro observations and suggests that delivery of a p12 murine gene suppresses tumor cell growth in vivo, with specific increases in TUNEL labeling and apoptotic indices and decreases in Ki-67 cell proliferation labeling indices as compared with controls, resulting in an antitumor effect in a manner that is consistent with a role as a tumor growth suppressor in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…Also, cell proliferation (proliferating cell nuclear antigen labeling index) was found to increase progressively through hamster oral malignant progression, whereas p12 expression levels progressively decreased through malignant progression (19). Finally, recent data using murine p12-targeted ES knockout clones (p12À/À) showed that in the absence of p12 expression, cellular proliferation is increased, with an increase in S phase and a decrease in G 2 -M phase populations, and apoptosis is significantly reduced with cisplatin treatment (20). In combination, these in vitro data support the role of p12 in regulating tumor cell phenotype and growth; however, specific examination of p12 antitumor effects had not been evaluated previously in vivo.…”

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confidence: 99%

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p12CDK2-AP1 Gene Therapy Strategy Inhibits Tumor Growth in an In vivo Mouse Model of Head and Neck Cancer

Figueiredo¹,

Kim²,

Marcus

et al. 2005

Clinical Cancer Research

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Purpose: To test the potential of p12 CDK2-AP1 (p12), a cell cycle regulator and cyclin-dependent kinase-2-associating protein commonly down-regulated in head and neck squamous cell carcinoma (f70%), as a gene therapy in inhibiting head and neck squamous cell carcinoma growth in vivo. Experimental Design: We addressed the effect of p12 expression on tumor growth by using a well-established squamous cell carcinoma VII/SF floor of mouth xenograft mouse model. The effect of therapy on tumor growth was determined for: (a) no treatment, (b) PBS, (c) vehicle (1,2-dioleoyloxy-3-trimethylammonium propane:cholesterol liposomes / 5 % dextrose), (d) empty vector controls, and (e) p12-encoding vector experimental groups. Results: p12 gene therapy significantly induced antitumor effects as compared with controls, including (a) size and weight of p12-treated tumors decreased by 51% to 72% compared with all controls (P < 0.02), (b) tumor growth rate post-therapy was inhibited by 55 % to 64% compared with empty vector controls (P < 0.0001), and (c) p12 expression was higher in p12-treated than controls (P < 0.002) by two-tailed t test analyses. Mechanistically, p12 treatment affected cell turnover kinetics as assessed by apoptotic and cell proliferation indices. p12 therapy significantly increased terminal nucleotidyl transferase^mediated nick end labeling (P < 0.05) and morphology-based apoptotic indices (P < 0.05) as well as significantly decreased Ki-67 cell proliferation indices (P < 0.001) compared with controls, resulting in a net cell turnover reduction in p12-treated tumors. Conclusions: We show that this novel therapeutic modality can significantly induce antitumor responses in vivo. These results support a role for p12 as a novel tumor growth suppressor gene therapy and suggest that optimization and/or combination with current therapies may hold considerable promise in preparation for clinical trials.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

p12CDK2-AP1 Gene Therapy Strategy Inhibits Tumor Growth in an In vivo Mouse Model of Head and Neck Cancer

Figueiredo¹,

Kim²,

Marcus

et al. 2005

Clinical Cancer Research

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“…Ϫ/Ϫ mESCsHeterozygous and homozygous Cdk2ap1 knock-out mESCs were generated as reported previously (13). We found the homozygous knock-out of Cdk2ap1 in mice resulted in the embryonic lethality at embryonic days 3.5-5.5 (22).…”

Section: Altered Differentiation Competency In Cdk2ap1mentioning

confidence: 99%

“…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). Recently, Cdk2ap1 has been identified as one of the stem cell-specific genes that are enriched in both embryonic and adult stem cells (16).…”

mentioning

confidence: 99%

“…p12 CDK2AP1 (CDK2AP1) is a highly conserved, ubiquitously expressed gene that is down-regulated in ϳ70% of oral cancers (10,11). 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).…”

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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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To control or to be controlled? Dual roles of CDK2 in DNA damage and DNA damage response

et al. 2020

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p12CDK2-AP1 mediates DNA damage responses induced by cisplatin

Cited by 16 publications

References 55 publications

p12CDK2-AP1 Gene Therapy Strategy Inhibits Tumor Growth in an In vivo Mouse Model of Head and Neck Cancer

p12CDK2-AP1 Gene Therapy Strategy Inhibits Tumor Growth in an In vivo Mouse Model of Head and Neck Cancer

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

To control or to be controlled? Dual roles of CDK2 in DNA damage and DNA damage response

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