Attenuation of BPDE-induced p53 accumulation by TPA is associated with a decrease in stability and phosphorylation of p53 and downregulation of NFkappaB activation: role of p38 MAP kinase.
Attenuation of BPDE-induced p53 accumulation by TPA is associated with a decrease in stability and phosphorylation of p53 and downregulation of NFkappaB activation: role of p38 MAP kinase.
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DOI：
10.1093/carcin/bgi247
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发表时间：
2006-03
期刊：
影响因子：
4.7
通讯作者：
J. J. Mukherjee-J.;H. Sikka
中科院分区：
文献类型：
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作者：
J. J. Mukherjee-J.;H. Sikka
苯并[a]芘（B[a]P）或其他多环芳烃（PAHs）引起的DNA损伤诱导p53蛋白作为一种保护措施，以消除DNA损伤的诱变固定的可能性。12-O-十四酰佛波醇-13-乙酸酯（TPA）抑制由B[a]P和其他DNA损伤剂诱导的p53反应，并可能导致肿瘤促进。TPA减弱B[a] P诱导的p53应答的分子机制尚不清楚。我们研究了TPA对（+/-）-anti-benzo[a]pyrene-7，8-diol-9，10-epoxide（BPDE）处理的小鼠表皮JB 6（P（+））Cl 41细胞中p53反应的影响。BPDE处理诱导p53积聚，TPA显著减弱p53积聚。用BPDE和TPA处理的细胞显示，与BPDE处理的细胞相比，在p53免疫沉淀物中Mdm 2与p53蛋白的比率增加，并且p53寿命降低，表明TPA使p53不稳定。TPA还抑制BPDE诱导的p53丝氨酸15磷酸化。ERK和p38 MAPK均被BPDE激活，而MEK 1/2或p38 MAPK的特异性抑制剂U 0126或SB 202190可减弱BPDE诱导的p53蓄积，表明ERK和p38 MAPK在p53蓄积中的作用。有趣的是，TPA增强了BPDE诱导的ERK激活，而TPA显著抑制了p38 MAPK激活，表明TPA对p38 MAPK的抑制与p53的衰减有关。此外，SB 202190处理引起BPDE处理的细胞中p53稳定性降低和p53在丝氨酸15处磷酸化的抑制。我们还观察到TPA或SB 202190减弱了BPDE诱导的携带NF κ B报告质粒的JB 6 Cl 41细胞中NF κ B的激活。据我们所知，这是TPA抑制化学致癌物诱导的NF κ B活化的第一份报告。TPA对BPDE诱导的NF κ B活化的干扰暗示p53功能的消除，这已经讨论过。总的来说，我们的数据表明，废除BPDE诱导的p53反应和NF κ B激活TPA介导的损伤的信号通路，涉及p38 MAPK。
DNA damage caused by benzo[a]pyrene (B[a]P) or other polynuclear hydrocarbons (PAHs) induce p53 protein as a protective measure to eliminate the possibility of mutagenic fixation of the DNA damage. 12-O-tetradecanoylphorbol-13-acetate (TPA) inhibits p53 response induced by B[a]P and other DNA-damaging agents and may cause tumor promotion. The molecular mechanism of attenuation of B[a]P-induced p53 response by TPA is not known. We investigated the effect of TPA on p53 response in (+/-)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE)-treated mouse epidermal JB6(P(+)) Cl 41 cells. BPDE treatment induced p53 accumulation which was attenuated significantly by TPA. Cells treated with BPDE and TPA showed increased ratio of Mdm2 to p53 proteins in p53 immunoprecipitate and decreased p53 life span compared to BPDE-treated cells indicating p53 destabilization by TPA. TPA also inhibited BPDE-induced p53 phosphorylation at serine15. Activation of both ERKs and p38 MAPK by BPDE and attenuation of BPDE-induced p53 accumulation by U0126 or SB202190, specific inhibitor of MEK1/2 or p38 MAPK, indicate the role of ERKs and p38 MAPK in p53 accumulation. Interestingly, TPA potentiated BPDE-induced activation of ERKs whereas p38 MAPK activation was significantly inhibited by TPA, suggesting that inhibition of p38 MAPK is involved in p53 attenuation by TPA. Furthermore, SB202190 treatment caused decreased p53 stability and inhibition of phosphorylation of p53 at serine15 in BPDE-treated cells. We also observed that TPA or SB202190 attenuated BPDE-induced nuclear factor kappa B (NFkappaB) activation in JB6 Cl 41 cells harboring NFkappaB reporter plasmid. To our knowledge this is the first report that TPA inhibits chemical carcinogen-induced NFkappaB activation. Interference of TPA with BPDE-induced NFkappaB activation implicates abrogation of p53 function which has been discussed. Overall, our data suggest that abrogation of BPDE-induced p53 response and of NFkappaB activation by TPA is mediated by impairment of the signaling pathway involving p38 MAPK.