DNA synthesis inhibition in response to benzo[a]pyrene dihydrodiol epoxide is associated with attenuation of p(34)cdc2: Role of p53.
DNA synthesis inhibition in response to benzo[a]pyrene dihydrodiol epoxide is associated with attenuation of p(34)cdc2: Role of p53.
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DOI：
10.1016/j.mrgentox.2013.05.009
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发表时间：
2013-07-04
影响因子：
1.9
通讯作者：
Kumar, Subodh
中科院分区：
文献类型：
--
作者：
Mukherjee, Jagat J.;Kumar, Subodh
关键词：
我们之前的研究结果表明，多核芳烃（PAHs）的DNA损伤引发了与p53蛋白（一种生长抑制转录因子）积累相关的人成纤维细胞生长抑制（G1-S细胞周期阻滞和DNA合成抑制）的细胞保护性反应。在这里，我们报道了BPDE（多环芳烃苯并[a]芘的最终致癌代谢物）处理引发了不同程度的DNA合成/细胞生长抑制，这与p53积累增加的程度不对应。BPDE处理的细胞显著减弱p34cdc2的表达，p34cdc2是一种细胞周期激活蛋白。虽然cdc2下调在抑制细胞周期进程中的作用是众所周知的，但cdc2下调对多环芳烃细胞损伤的反应尚未报道。与p53积累不同，BPDE对DNA合成/细胞生长的抑制与cdc2下调之间存在对应关系。bpde诱导的cdc2下调依赖于p53，尽管p53积累与cdc2下调之间没有对应关系。bpde诱导的cdc2下调与细胞周期抑制蛋白p21 （p53的反激活产物）的积累相对应。DNA损伤多环芳烃对DNA合成/细胞生长的抑制可能涉及p53激活介导的cdc2蛋白的下调（反活化能力），p53积累的程度并不是这方面的唯一决定因素。
Our previous findings demonstrated that DNA damage by polynuclear aromatic hydrocarbons (PAHs) triggers a cellular protective response of growth inhibition (G1-S cell cycle arrest and inhibition of DNA synthesis) in human fibroblasts associated with accumulation of p53 protein, a growth-inhibitory transcription factor. Here, we report that BPDE (the ultimate carcinogenic metabolite of the PAH benzo[a]pyrene) treatment triggers a variable extent of inhibition of DNA synthesis/cell growth, which does not correspond to the extent of increased p53 accumulation. BPDE treatment of cells significantly attenuates expression of p34cdc2, a cell cycle activating protein. Although the role of cdc2 down-regulation in inhibition of cell cycle progression is well known, cdc2 down-regulation in response to cellular insult by PAHs has not been reported. Unlike p53 accumulation, there is a correspondence between DNA synthesis/cell growth inhibition and cdc2 down-regulation by BPDE. BPDE-induced cdc2 down-regulation is p53 dependent, although there is no correspondence between p53 accumulation and cdc2 down-regulation. BPDE-induced cdc2 down-regulation corresponded with accumulation of the cell cycle inhibitor protein p21 (transactivation product of p53). DNA synthesis/cell growth inhibition in response to DNA-damaging PAHs may involve down-regulation of cdc2 protein mediated by p53 activation (transactivation ability), and the extent of p53 accumulation is not the sole determining factor in this regard.
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