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Attenuation of p53 Response to PAHs by Tumor Promoters

肿瘤启动子减弱 p53 对 PAH 的反应

基本信息

批准号：
6556149
负责人：
JAGAT J MUKHERJEE
金额：
$ 14.72万
依托单位：
BUFFALO STATE COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-30 至 2005-09-29
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): There is considerable evidence showing that the prototype polynuclear aromatic hydrocarbon (PAH) benzo[a] pyrene (BP) induces p53 in human and mouse cells, and that 12-O-tetradecanoylphorbol-13-acetate (TPA) and other tumor promoters attenuate this BP-induced p53 up-regulation. We hypothesize that the inhibition of p53 accumulation by TPA is due to (i) inhibition of BP-induced p53 transcription which is activated by nuclear factor kappaB (NF-kappaB) and (ii) decreased p53 protein stability, which is regulated by mouse double minute (MDM) 2 protein level and post-translational modifications of p53 and MDM2 proteins by signal transducing kinase-mediated phosphorylations. We have selected mouse epidermal JB6 (P+) cells and (+)-anti-BPDE (BP-derived ultimate carcinogen) for the proposed study. In order to test the above hypotheses, we propose (i) to investigate the effect of TPA on p53 transcript/protein levels, p53 protein stability and NF-kappaB activation in cells treated with (+)-anti-BPDE, (ii) to examine the effect of TPA on MDM2 protein expression and stability, (iii) to examine the effect of TPA on the activation of PI3-kinase and Akt (involved in mdm2 protein phosphorylation) in relation to p53 response and (iv) to determine the effect of TPA on the activation of ERK1/2 and PKC (involved in p53 protein phosphorylations) in relation to p53 response. The overall objective of the proposed research is to understand the mechanism by which TPA inhibits the (+)-anti-BPDE -induced up-regulation of p53, and thereby elucidate the mechanism(s) underlying the promotion of PAH-induced carcinogenicity by TPA and possibly other tumor promoters.

描述（由申请人提供）：有大量证据表明原型多核芳香烃（PAH）苯并[a]芘（BP）在人和小鼠细胞中诱导p53，并且12-O-十四烷酰佛波醇-13-乙酸酯（TPA）和其他肿瘤促进剂减弱这种BP诱导的p53上调。我们假设 TPA 对 p53 积累的抑制是由于 (i) 抑制由核因子 kappaB (NF-kappaB) 激活的 BP 诱导的 p53 转录，以及 (ii) 降低 p53 蛋白稳定性，该稳定性受小鼠双微体 (MDM) 2 蛋白水平以及 p53 和 MDM2 蛋白通过信号转导的翻译后修饰调节激酶介导的磷酸化。我们选择了小鼠表皮 JB6 (P+) 细胞和 (+)-抗 BPDE（BP 衍生的最终致癌物）用于拟议的研究。为了检验上述假设，我们建议 (i) 研究 TPA 对 (+)-anti-BPDE 处理的细胞中 p53 转录物/蛋白水平、p53 蛋白稳定性和 NF-kappaB 激活的影响，(ii) 检查 TPA 对 MDM2 蛋白表达和稳定性的影响，(iii) 检查 TPA 对 PI3 激酶和 Akt 激活的影响（参与 mdm2 蛋白磷酸化）与 p53 反应相关，以及 (iv) 确定 TPA 对与 p53 反应相关的 ERK1/2 和 PKC（参与 p53 蛋白磷酸化）激活的影响。本研究的总体目标是了解 TPA 抑制 (+)-抗 BPDE 诱导的 p53 上调的机制，从而阐明 TPA 和可能的其他肿瘤促进剂促进 PAH 诱导致癌性的潜在机制。