Multiple roles of the tumor suppressor p53

Bargonetti, Jill; Manfredi, James J.

doi:10.1097/00001622-200201000-00015

Cited by 309 publications

(216 citation statements)

References 58 publications

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“…The p53 protein plays a central role in the control of cell cycle progression or apoptotic cell death (Bargonetti and Manfredi 2002;Levine 1997;Vousden 2000). Therefore, there is a possibility that cell cycle arrest (Levresse et al 1997) and apoptosis (Aikoh et al 1998;Broaddus et al 1996;Dopp et al 1995;Hamilton et al 1996;Wu et al 2000) found in cells exposed to chrysotile might be caused by an activated form of p53 protein.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…The p53 tumor suppressor protein plays an important role in the control of genomic integrity or the elimination of damaged or tumorigenic cells (Bargonetti and Manfredi 2002;Levine 1997;Vousden 2000). The mutational inactivation of p53 protein is one of the most common genetic events that occur in human cancers (Hupp et al 2000).…”

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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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“…The p53 reaction to cellular damage triggers several types of responses, ranging from stopping the cell cycle to induction of apoptosis (31,32). Thus, the p53 pathway plays a central role in cancer biology (32,33), being at the center of all processes implicated in the cellular response to genotoxic stress (25). The p53 protein contributes to proliferation by its participation in the checkpoints that controls the cell cycle (34)(35)(36).…”

Section: Introductionmentioning

confidence: 99%

VRK1 Signaling Pathway in the Context of the Proliferation Phenotype in Head and Neck Squamous Cell Carcinoma

Santos

Rodríguez-Pinilla²,

Vega

et al. 2006

Molecular Cancer Research

105

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The vaccinia-related kinase (VRK) proteins are a new family with three members in the human kinome. The VRK1 protein phosphorylates several transcription factors and has been postulated to be involved in regulation of cell proliferation. In normal squamous epithelium, VRK1 is expressed in the proliferation area. Because VRK1 can stabilize p53, the expression of the VRK1 protein was analyzed in the context of the p53 pathway and the proliferation phenotype in a series of 73 head and neck squamous cell carcinomas. VRK1 protein level positively correlated with p53 response proteins, particularly hdm2 and p21. The VRK1 protein also correlated positively with several proteins associated with proliferation, such as cyclin-dependent kinase 2 (CDK2), CDK6, cdc2, cyclins B1 and A, topoisomerase II, survivin, and Ki67. The level of VRK1 protein behaves like a proliferation marker in this series of head and neck squamous cell carcinomas. To identify a possible regulatory role for VRK1 and because it regulates gene transcription, the promoters of two genes were studied, CDK2 and SURVIVIN, whose proteins correlated positively with VRK1. VRK1 increases the activity of both the CDK2 and SURVIVIN gene promoters. The expression of VRK1 was analyzed in the context of regulators of the G 1 -S transition. VRK1 protein levels increase in response to E2F1 and are reduced by retinoblastoma and p16. These data suggest that VRK1 might play a role in cell cycle regulation and is likely to represent the beginning of a new control mechanism of cell cycle, particularly late in the G 1 -S phase.

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“…The tumor suppressor p53 is a master regulator of apoptosis in many types of cells (Shen and White, 2001;Bargonetti and Manfredi, 2002;Vousden and Lu, 2002;Manfredi, 2003;Oren, 2003). Loss of functional p53 is sufficient to inactivate the apoptotic machinery in many types of tumor cells as well as nontumor cells (Shen and White, 2001).…”

Section: Introductionmentioning

confidence: 99%

Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities

et al. 2006

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We have previously demonstrated that the serine/threonine protein phosphatase-1 (PP-1) plays an important role in promoting cell survival. However, the molecular mechanisms by which PP-1 promotes survival remain largely unknown. In the present study, we provide evidence to show that PP-1 can directly dephosphorylate a master regulator of apoptosis, p53, to negatively modulate its transcriptional and apoptotic activities, and thus to promote cell survival. As a transcriptional factor, the function of p53 can be greatly regulated by phosphorylation and dephosphorylation. While the kinases responsible for phosphorylation of the 17 serine/threonine sites have been identified, the dephosphorylation of these sites remains largely unknown. In the present study, we demonstrate that PP-1 can dephosphorylate p53 at Ser-15 and Ser-37 through co-immunoprecipitation, in vitro and in vivo dephosphorylation assays, overexpression and silence of the gene encoding the catalytic subunit for PP-1. We further show that mutations mimicking constitutive dephosphorylation or phosphorylation of p53 at these sites attenuate or enhance its transcriptional activity, respectively. As a result of the changed p53 activity, expression of the downstream apoptosis-related genes such as bcl-2 and bax is accordingly altered and the apoptotic events are either largely abrogated or enhanced. Thus, our results demonstrate that PP-1 directly dephosphorylates p53, and dephosphorylation of p53 has as important impact on its functions as phosphorylation does. In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway.

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Multiple roles of the tumor suppressor p53

Cited by 309 publications

References 58 publications

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

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

VRK1 Signaling Pathway in the Context of the Proliferation Phenotype in Head and Neck Squamous Cell Carcinoma

Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities

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