Cancer Susceptibility Polymorphism of p53 at Codon 72 Affects Phosphorylation and Degradation of p53 Protein

Ozeki, Chikako; Sawai, Yuichiro; Shibata, Tatsuhiro; Okamoto, Koji; Yokota, Jun; Tashiro, Fumio; Tanuma, Sei–ichi; Sakai, Ryuichi; Kawase, Tatsuya; Kitabayashi, Issay; Ohki, Rieko

doi:10.1074/jbc.m110.208587

Cited by 26 publications

(24 citation statements)

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“…The Arg/Pro genotype of p53 codon 72 singly as well as in combination with Pro/Pro genotypes conferred protection towards oral cancer development. There are evidences that the codon 72 polymorphism had a profound effect on the primary structure of p53 protein and its biochemical and biological activities (Matlashewski et al, 1987;Ozeki et al, 2011). It has been shown that the Pro-72 form of p53 has increased transcriptional trans-activation capacity, induces a higher level of G1 arrest and senescence compared to the Arg-72 form (Thomas et al, 1999;Pim and Banks 2004;Frank et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Association between p53 Gene Variants and Oral Cancer Susceptibility in Population from Gujarat, West India

Patel

Vajaria²,

Begum³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Background: p53 gene variants i.e. 16 bp duplication in intron 3, Arg72Pro in exon 4 and G>A in intron 6 have been reported to modulate susceptibility to various malignancies. Therefore, the present study evaluated the role of these p53 polymorphisms in oral cancer susceptibility in a population from Gujarat, West India. Method: Genotype frequencies at the three p53 loci in 110 controls and 79 oral cancer cases were determined by the PCR-RFLP method. Results: Heterozygous individuals at exon 4 showed protection from developing oral cancer. Homozygous wild and heterozygous individuals at intron 3 and those heterozygous at exon 4 in combination appeared to be at lowered risk. Furthermore, carriers of the 16 bp duplication allele at intron 3, proline allele at exon 4 and G allele at intron 6 were protected from oral cancer development. Conclusion: p53 polymorphisms, especially Arg72Pro in exon 4 could significantly modify the risk of oral cancer development in Gujarat, West Indian population.

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Section: Discussionmentioning

confidence: 99%

Association between p53 Gene Variants and Oral Cancer Susceptibility in Population from Gujarat, West India

Patel

Vajaria²,

Begum³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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“…The p53 polymorphic variants p53Pro and p53Arg differ in regulating the p53 dependent cell processes, such as a cell cycle arrest, DNA repair, programmed cell death induction, aging, and hypoxia resistance [7].…”

Section: Introductionmentioning

confidence: 99%

Linkage disequilibrium and haplotypes of the rs1042522, rs1625895, and rs1787862 markers of TP53 in patients with diffuse large B-cell lymphoma

et al. 2014

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The association of the rs1042522, rs17878362, and rs1625895 polymorphisms of TP53 with risk of non Hodgkin's lymphoma (NHL) has not been studied in full detail. NHL has many variants, and each indi vidual polymorphism exerts only a minor effect, requiring the polymorphisms to be studied for particular his tological subtypes of lymophomas and as components of haplotype groups. The objective of this work was to analyze the frequencies and linkage disequilibrium for rs1042522, rs1625895, and rs17878362 and their com bined haplotype in patients with diffuse large B cell lymphoma (DLBCL) and control subjects. Differences in linkage disequilibrium structure were observed for rs17878362, rs1042522, and rs1625895 in the Siberian population. The haplotype proved to be more informative than the individual TP53 polymorphisms in a case-control association analysis in DLBCL. Haplotype wArgG was associated with predisposition to DLBCL, while haplotypes wProG and dupProG were found to exert a protective effect. The effect of the hap lotype at three TP53 polymorphisms was observed to vary depending on their homozygous or heterozygous state.

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“…20), RIN (rat pancreatic β cell), and MIN6 (mouse pancreatic β cell). Cell culture and transfection was performed as described (21). The siRNAs were introduced using RNAiMAX (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

PHLDA3 is a novel tumor suppressor of pancreatic neuroendocrine tumors

Ohki¹,

Saito

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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122

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The molecular mechanisms underlying the development of pancreatic neuroendocrine tumors (PanNETs) have not been well defined. We report here that the genomic region of the PHLDA3 gene undergoes loss of heterozygosity (LOH) at a remarkably high frequency in human PanNETs, and this genetic change is correlated with disease progression and poor prognosis. We also show that the PHLDA3 locus undergoes methylation in addition to LOH, suggesting that a two-hit inactivation of the PHLDA3 gene is required for PanNET development. We demonstrate that PHLDA3 represses Akt activity and Akt-regulated biological processes in pancreatic endocrine tissues, and that PHLDA3-deficient mice develop islet hyperplasia. In addition, we show that the tumor-suppressing pathway mediated by MEN1, a well-known tumor suppressor of PanNETs, is dependent on the pathway mediated by PHLDA3, and inactivation of PHLDA3 and MEN1 cooperatively contribute to PanNET development. Collectively, these results indicate the existence of a novel PHLDA3-mediated pathway of tumor suppression that is important in the development of PanNETs.p53 | PH domain | everolimus | p53 target gene | mTOR N euroendocrine tumors (NETs) arise from cells of the endocrine and nervous systems, and are found in tissues such as lung, pancreas and pituitary (1-3). NETs often produce, store and release biogenic amines and polypeptide hormones, and secretary granules containing these products provide a diagnostic marker for NETs. The mechanisms underlying the development of NETs remain unclear to date, due to the low incidence of these tumors and due to the lack of suitable experimental model systems, including genetically engineered mouse models. Pancreatic NET (PanNET), which is probably the best-studied NET, is the second-most common pancreatic tumor, having an incidence of ∼1 per 100,000 individuals. Patients having late-stage PanNET often harbor tumors that are unresectable or metastatic and face limited treatment options. Accordingly, the prognosis of patients having metastatic PanNET is the worst among the NET subtypes, with a 5-y survival rate of 27-43% (1). Recently, the drug Everolimus has shown promise in the treatment of PanNETs (4), providing a significant improvement in progression-free survival. Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), a downstream mediator of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway. The striking efficacy of Everolimus demonstrates the importance of the PI3K/Akt pathway in the pathology of PanNETs.In agreement with these clinical results, studies on pancreatic endocrine cell lines have identified the PI3K/Akt signaling pathway as a major proliferation and survival pathway in these cells (5). Activated Akt phosphorylates substrates such as mTOR and controls various biological processes, including protein synthesis, proliferation, cell growth, and survival. Regulation of pancreatic islet β-cell proliferation, cell size, and apoptosis by Akt has been demonstrated using various mouse models. For examp...

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Cancer Susceptibility Polymorphism of p53 at Codon 72 Affects Phosphorylation and Degradation of p53 Protein

Cited by 26 publications

References 26 publications

Association between p53 Gene Variants and Oral Cancer Susceptibility in Population from Gujarat, West India

Association between p53 Gene Variants and Oral Cancer Susceptibility in Population from Gujarat, West India

Linkage disequilibrium and haplotypes of the rs1042522, rs1625895, and rs1787862 markers of TP53 in patients with diffuse large B-cell lymphoma

PHLDA3 is a novel tumor suppressor of pancreatic neuroendocrine tumors

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