Mechanism of p53-dependent Apoptosis Induced by 3-Methylcholanthrene

Kwon, Yong-Won; Ueda, Shugo; Ueno, Masaya; Yodoi, Junji; Masutani, Hiroshi

doi:10.1074/jbc.m105033200

Cited by 81 publications

(56 citation statements)

References 38 publications

(32 reference statements)

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“…Especially, the phosphorylation of p53 at serine 15 was reported to be a key phosphorylation target during the p53 activation process to apoptotic cell death [16,17]. Of the MAPK families, p53 can be phosphorylated either directly or indirectly by p38 kinase [18][19][20][21] and JNK [22,23]. Compared to several studies on the role of p38 kinase or JNK in p53 regulation, there is less evidence to indicate phosphorylation and/or accumulation of p53 by ERK.…”

Section: Discussionmentioning

confidence: 86%

Melatonin Induces Apoptotic Cell Death via p53 in LNCaP Cells

Kim

Yoo

2010

Korean J Physiol Pharmacol

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In this study, we examined whether melatonin promotes apoptotic cell death via p53 in prostate LNCaP cells. Melatonin treatment significantly curtailed the growth of LNCaP cells in a dose-and time-dependent manner. Melatonin treatment (0 to 3 mM) induced the fragmentation of poly(ADPribose) polymerase (PARP) and activation of caspase-3, caspase-8, and caspase-9. Moreover, melatonin markedly activated Bax expression and decreased Bcl-2 expression in dose increments. To investigate p53 and p21 expression, LNCaP cells were treated with 0 to 3 mM melatonin. Melatonin increased the expressions of p53, p21, and p27. Treatment with mitogen-activated protein kinase (MAPK) inhibitors, PD98059 (ERK inhibitor), SP600125 (JNK inhibitor) and SB202190 (p38 inhibitor), confirmed that the melatonin-induced apoptosis was p21-dependent, but ERK-independent. W ith the co-treatment of PD98059 and melatonin, the expression of p-p53, p21, and MDM2 did not decrease. These effects were opposite to the expression of p-p53, p21, and MDM2 observed with SP600125 and SB202190 treatments. Together, these results suggest that p53-dependent induction of JNK/p38 MAPK directly participates in apoptosis induced by melatonin.

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Section: Discussionmentioning

confidence: 86%

Melatonin Induces Apoptotic Cell Death via p53 in LNCaP Cells

Kim

Yoo

2010

Korean J Physiol Pharmacol

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“…Exposure to chrysotile has been reported to activate ERK in rat pleural mesothelial cells in vitro (Zanella et al 1996) and mouse pulmonary epithelial cells in vivo (Robledo et al 2000), although its effects on p38 and JNK are not known. On the other hand, Ser15 phosphorylation induced by various cellular stimuli such as ultraviolet radiation (Bulavin et al 1999;She et al 2000), cisplatin (Persons et al 2000), L-thyroxine (Shih et al 2001), chromium (Wang and Shi 2001), resveratrol (She et al 2001), and 3-methylcholanthrene (Kwon et al 2002) has been reported to be mediated by ERK and/or p38. However, in the present study, treatment with neither U0126 nor SB203580 suppressed chrysotile-induced Ser15 phosphorylation, indicating it is unlikely that ERK and p38 are responsible for p53 phosphorylation at Ser15 in A549 cells exposed to chrysotile.…”

Section: Discussionmentioning

confidence: 99%

“…Members of the phosphatidylinositol 3-kinase-related kinase (PIKK) family such as DNA-activated protein kinase (DNA-PK) and ataxia-telangiectasia mutated (ATM) have been implicated in the phosphorylation of p53 at Ser15 (Giaccia and Kastan 1998;Lakin and Jackson 1999;Meek 1998). Furthermore, extracellular signal-regulated protein kinase (ERK) and p38, the members of mitogenactivated protein kinase (MAPK), have been reported to induce p53 phosphorylation at Ser15 (Bulavin et al 1999;Kwon et al 2002;Persons et al 2000;She et al 2000She et al , 2001Shih et al 2001;Wang and Shi 2001).…”

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confidence: 99%

Phosphorylation of p53 protein in A549 human pulmonary epithelial cells exposed to asbestos fibers.

Matsuoka

Ichikawa

Morimoto

2003

Environ Health Perspect

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We examined effects of asbestos exposure on the phosphorylation of p53 protein in human pulmonary epithelial type II cells (A549), which express wild-type p53. In cells exposed to two different types of asbestos, chrysotile (approximately 1-6% iron content) and crocidolite (approximately 27% iron content) fibers, at the doses of 1, 5, and 10 microg/cm2 for 24 hr, the levels of p53 phosphorylated at Ser15 and p53 protein were correlated with the dose. On a per-weight basis, chrysotile was more potent in inducing Ser15 phosphorylation and accumulation of p53 protein than was crocidolite. After exposure to 10 micro g/cm2 chrysotile, the levels of p53 phosphorylated at Ser15 and of p53 protein increased after 18 hr. Among serines in p53 protein immunoprecipitated from A549 cells treated with chrysotile, only Ser15 was markedly phosphorylated. In contrast, no clear phosphorylation was observed at Ser6, Ser9, Ser20, Ser37, Ser46, or Ser392. Blocking of the extracellular signal-regulated protein kinase pathway with U0126 or inhibition of p38 activity with SB203580 did not suppress chrysotile-induced Ser15 phosphorylation. On the other hand, treatment with wortmannin, an inhibitor of DNA-activated protein kinase and ataxia-telangiectasia mutated, suppressed both chrysotile-induced Ser15 phosphorylation and accumulation of p53 protein. Treatment with either catalase or N-acetylcysteine failed to suppress chrysotile-induced Ser15 phosphorylation, suggesting that reactive oxygen species do not play a major role in the phosphorylation of p53 protein. The present results show that asbestos, particularly chrysotile, induces phosphorylation of p53 protein at Ser15 in A549 cells depending on a DNA damage-signaling pathway.

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“…18,19 Ser15 phosphorylation could result in the accumulation of p53 via inhibition of MDM2 interaction and protein degradation. 12,20 Both Ser15 and 20 appear to be important at least in the regulation of p53-mediated apoptosis. 21 Analysis of individual mutants revealed that mutations in these specific residues of p53 are primarily responsible for impairment of its apoptotic activity.…”

Section: Control Loading Is Shown By Actinmentioning

confidence: 99%

Apoptosis and growth arrest induced by platinum compounds in U2-OS cells reflect a specific DNA damage recognition associated with a different p53-mediated response

et al. 2002

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Mononuclear and multinuclear platinum complexes are known to induce distinct types of DNA lesions and exhibit different profiles of antitumor activity, in relation to p53 mutational status. In this study, we investigated the cellular effects of exposure to two platinum compounds (cisplatin and the multinuclear platinum complex BBR 3464), in the osteosarcoma cell line, U2-OS, carrying the wild-type p53 gene and capable of undergoing apoptosis or cell cycle arrest in response to diverse genotoxic stresses. In spite of the ability of both compounds to up-regulate p53 at cytotoxic concentrations, exposure to BBR 3464 resulted in cell cycle arrest but only cisplatin was capable of inducing significant levels of apoptosis and phosphorylation at the Ser15 residue of p53. The cisplatin-induced protein phosphorylation, not detectable in cells treated with BBR 3464, was associated with RPA phosphorylation, a specific up-regulation of Bax and downregulation of p21 WAF1 . Cells treated with BBR 3464 displayed a different cellular response with evidence of cytostasis associated with a high induction of p21 WAF1 . The regulation of p21 WAF1 after cisplatin or BBR 3464 exposure required a p53 signal, as documented using stable transfectants expressing a dominant-negative form of p53 (175 his ). Taken together, these results indicate that cellular response to different genotoxic lesions (i.e. apoptosis or growth arrest) is associated with a specific recognition of DNA damage and a different p53-mediated signaling pathway. Multinuclear platinum complexes could be regarded as useful tools for investigating the p53-mediated process of cell cycle arrest in response to DNA damage.

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Mechanism of p53-dependent Apoptosis Induced by 3-Methylcholanthrene

Cited by 81 publications

References 38 publications

Melatonin Induces Apoptotic Cell Death via p53 in LNCaP Cells

Melatonin Induces Apoptotic Cell Death via p53 in LNCaP Cells

Phosphorylation of p53 protein in A549 human pulmonary epithelial cells exposed to asbestos fibers.

Apoptosis and growth arrest induced by platinum compounds in U2-OS cells reflect a specific DNA damage recognition associated with a different p53-mediated response

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