Expression of p53 gene in hepatocellular carcinomas induced by aflatoxin B1 with or without human hepatitis B virus in tree shrews

Su, Jianjia; Qin, Guozhong; Ruiqi, Yan; Huang, Dingrui; Yang, Chun; Huang, Guohua; Lotlikar, Prabhakar D.

doi:10.1038/emm.1997.27

Cited by 5 publications

(3 citation statements)

References 29 publications

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“…This could be explained at least in part by the in general low expression of p53 in normal livers. 76 During HCC development, the expression levels of p53 tend to increase, 77 and in particular it may undergo multiple rounds of mutation. 78 Whether the low glucose-triggered Ser46-specific phosphorylation may have functions in addition to induction of apoptosis, such as causation of cell cycle arrest, induction of immune response and hepatic fibrosis, or regulation of stemness of hepatic progenitor cells and HCC stem cells during HCC formation (as does the p53 protein; reviewed in refs.…”

Section: Discussionmentioning

confidence: 99%

Low glucose metabolite 3-phosphoglycerate switches PHGDH from serine synthesis to p53 activation to control cell fate

Wu,

Zhang,

Xiong

et al. 2023

Cell Res

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Glycolytic intermediary metabolites such as fructose-1,6-bisphosphate can serve as signals, controlling metabolic states beyond energy metabolism. However, whether glycolytic metabolites also play a role in controlling cell fate remains unexplored. Here, we find that low levels of glycolytic metabolite 3-phosphoglycerate (3-PGA) can switch phosphoglycerate dehydrogenase (PHGDH) from cataplerosis serine synthesis to pro-apoptotic activation of p53. PHGDH is a p53-binding protein, and when unoccupied by 3-PGA interacts with the scaffold protein AXIN in complex with the kinase HIPK2, both of which are also p53-binding proteins. This leads to the formation of a multivalent p53-binding complex that allows HIPK2 to specifically phosphorylate p53-Ser46 and thereby promote apoptosis. Furthermore, we show that PHGDH mutants (R135W and V261M) that are constitutively bound to 3-PGA abolish p53 activation even under low glucose conditions, while the mutants (T57A and T78A) unable to bind 3-PGA cause constitutive p53 activation and apoptosis in hepatocellular carcinoma (HCC) cells, even in the presence of high glucose. In vivo, PHGDH-T57A induces apoptosis and inhibits the growth of diethylnitrosamine-induced mouse HCC, whereas PHGDH-R135W prevents apoptosis and promotes HCC growth, and knockout of Trp53 abolishes these effects above. Importantly, caloric restriction that lowers whole-body glucose levels can impede HCC growth dependent on PHGDH. Together, these results unveil a mechanism by which glucose availability autonomously controls p53 activity, providing a new paradigm of cell fate control by metabolic substrate availability.

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Section: Discussionmentioning

confidence: 99%

Low glucose metabolite 3-phosphoglycerate switches PHGDH from serine synthesis to p53 activation to control cell fate

Wu,

Zhang,

Xiong

et al. 2023

Cell Res

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“…Mutation of the p53 gene alters the conformation of the nuclear protein product, which can inactivate wild-type p53 protein16.The longer half life of the mutant p53 protein results in the accumulation of this phosphoprotein in the nuclei, facilitating its detection by immunohistochemical analysis 17 . Elevated expression of the p53 protein or mutational inactivation of the p53 gene has been shown in various human malignant tumors including carcinoma of colon and rectum 18,19 , breast 20 , prostate 21 , lung 22 , stomach 16 , thyroid 23 , and liver 24 . In colorectal carcinoma the occurrence of p53 mutation is variable among different series and has been found in 50% to 70% of cases 13,18 .…”

Section: Discussionmentioning

confidence: 99%

13- Immunohistochemical Analysis of P53 Protein in Colorectal Carcinoma and Its Relationship to Clinicopathologic Features

2011

Basrah Journal of Surgery

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Colorectal cancer regarded as one of the most widespread malignant tumor in the world. It is considered the second leading death factor among people in some developed countries. Colorectal cancer comprises several distinct histological types including adenocarcinoma which forms 85%-95% of all colorectal cancer cases. Pathogenesis of colorectal cancer is a multistep process characterized by involvement of many genetic alterations, including p53. The aim of this study is to detect the expression of p53 protein in colorectal carcinoma and to show its relationship with some clinicopathological features including age, gender, histological types, histological grades and staging. Forty paraffin-embedded tissue blocks of colectomy specimens were used in this retrospective study. They were collected from the Department of Pathology in Sulaimania Teaching Hospital, Shorsh Hospital and Shehid Saifeddin Private Clinic from January 2007 to July 2008. Two sections of 4 micrometer thickness were taken from each paraffin embedded tissue block. First section was taken for hematoxylin and eosin stain and the other one for immunohistochemistry [anti-p53 monoclonal antibody] by using DakoCytomation Envision + Dual Link System-HRP (DAB+). The relationship between p53 over expression and the dependent variable (age, gender, histological types, histological grades, and staging) were evaluated statistically using an analysis of variance (ANOVA) with STATA 8 soft ware (College station, Tx). A positive reaction for p53 was scored on a semiquantitative base as score 0 (no staining), score 1+ (weak staining), score 2+ (moderate staining), and score 3+ (strong staining). Staining was negative for p53 (score 0) in 16 cases (40%). Positive cases were scored as (1+) in 4 cases (10.0%); (2+) in 8 cases (20.0%); and (3+), in 12 cases (30.0%). There were no significant relationships between p53 over expression and age (p=0.682), gender (p=0.924), histological types (p=0.30), histological grades (p=0.516), and the stage of the disease (p=0.281). Conclusions: Considering the p53 protein over expression in a relatively high percentage of patients, it seems that p53 mutation may play an important role in the development of colorectal carcinoma. There were no significant relationships between p53 protein expression and some clinicopathologic variables such as age, gender, histological types, histological grades, and the stage of the disease.

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“…Furthermore, with the exception of the chimpanzee, tree shrew is the only known animal that can be infected with human HBV. Therefore, the application of tree shrew in research related to liver cancer and hepatitis is receiving increasing attentions and a number of works have been published [48][49][50][51][52] . Because of the difficulties in raising tree shrews artificially, most of the tree shrews used so far for research in China are captured individually from Yunnan Province.…”

Section: Specialist Commentarymentioning

confidence: 99%

Chemopreventive effect of oltipraz on AFB₁-induced hepatocarcinogenesis in tree shrew model

Qin

et al. 2000

WJG

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Expression of p53 gene in hepatocellular carcinomas induced by aflatoxin B1 with or without human hepatitis B virus in tree shrews

Cited by 5 publications

References 29 publications

Low glucose metabolite 3-phosphoglycerate switches PHGDH from serine synthesis to p53 activation to control cell fate

Low glucose metabolite 3-phosphoglycerate switches PHGDH from serine synthesis to p53 activation to control cell fate

13- Immunohistochemical Analysis of P53 Protein in Colorectal Carcinoma and Its Relationship to Clinicopathologic Features

Chemopreventive effect of oltipraz on AFB₁-induced hepatocarcinogenesis in tree shrew model

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Expression of p53 gene in hepatocellular carcinomas induced by aflatoxin B1 with or without human hepatitis B virus in tree shrews

Cited by 5 publications

References 29 publications

Low glucose metabolite 3-phosphoglycerate switches PHGDH from serine synthesis to p53 activation to control cell fate

Low glucose metabolite 3-phosphoglycerate switches PHGDH from serine synthesis to p53 activation to control cell fate

13- Immunohistochemical Analysis of P53 Protein in Colorectal Carcinoma and Its Relationship to Clinicopathologic Features

Chemopreventive effect of oltipraz on AFB1-induced hepatocarcinogenesis in tree shrew model

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Chemopreventive effect of oltipraz on AFB₁-induced hepatocarcinogenesis in tree shrew model