Mechanism of p53-dependent apoptosis induced by 3-methylcholanthrene: involvement of p53 phosphorylation and p38 MAPK.
Polycyclic aromatic hydrocarbons (PAHs) such as 3-methylcholanthrene (MC) cause untoward effects including carcinogenesis. Here we investigated the effect of MC on apoptosis. MC induced apoptosis, preceded by serine 15 phosphorylation and accumulation of p53. MC failed to cause apoptosis in p53-deficient MG63 cells, whereas ectopic expression of p53 in MG63 cells restored the response to MC. Therefore, MC-induced apoptosis was dependent on p53. MC also activated p38 mitogen-activated protein kinase (MAPK) at 16-24 h. Accumulation of p53 and p53 phosphorylated at serine 15 was not changed by SB203580, a specific inhibitor of p38 MAPK or overexpression of a dominant negative mutant of p38 MAPK at 8 h after MC treatment, whereas the accumulation was suppressed at 24 h. These results suggest that MC induces accumulation and phosphorylation of p53 via a p38 MAPK-independent (early) and p38 MAPK-dependent (late) pathway. SB203580 repressed MC-induced apoptosis. MC induced p38 MAPK activation in p53 expressing cells but not in p53-deficient cells, indicating that the p38 MAPK activation was dependent on early p53 activation. The current study shows that both p53 and p38 MAPK activation are required for MC-induced apoptosis and provides a novel model of a functional regulation between p53 and p38 MAPK in chemical stress-induced apoptosis.
Kwon
Yong-Won
YW
Institute for Virus Research, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Ueda
Shugo
S
Ueno
Masaya
M
Yodoi
Junji
J
Masutani
Hiroshi
H
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D008748:Methylcholanthrene / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
D016159:Tumor Suppressor Protein p53; D008748:Methylcholanthrene; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases