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Increases in p53 expression induce CTGF synthesis by mouse and human hepatocytes and result in liver fibrosis in mice
Takahiro Kodama, … , Masaki Mori, Norio Hayashi
Takahiro Kodama, … , Masaki Mori, Norio Hayashi
Published July 11, 2011
Citation Information: J Clin Invest. 2011;121(8):3343-3356. https://doi.org/10.1172/JCI44957.
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Research Article Hepatology

Increases in p53 expression induce CTGF synthesis by mouse and human hepatocytes and result in liver fibrosis in mice

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Abstract

The tumor suppressor p53 has been implicated in the pathogenesis of non-cancer-related conditions such as insulin resistance, cardiac failure, and early aging. In addition, accumulation of p53 has been observed in the hepatocytes of individuals with fibrotic liver diseases, but the significance of this is not known. Herein, we have mechanistically linked p53 activation in hepatocytes to liver fibrosis. Hepatocyte-specific deletion in mice of the gene encoding Mdm2, a protein that promotes p53 degradation, led to hepatocyte synthesis of connective tissue growth factor (CTGF; the hepatic fibrogenic master switch), increased hepatocyte apoptosis, and spontaneous liver fibrosis; concurrent removal of p53 completely abolished this phenotype. Compared with wild-type controls, mice with hepatocyte-specific p53 deletion exhibited similar levels of hepatocyte apoptosis but decreased liver fibrosis and hepatic CTGF expression in two models of liver fibrosis. The clinical significance of these data was highlighted by two observations. First, p53 upregulated CTGF in a human hepatocellular carcinoma cell line by repressing miR-17-92. Second, human liver samples showed a correlation between CTGF and p53-regulated gene expression, which were both increased in fibrotic livers. This study reveals that p53 induces CTGF expression and promotes liver fibrosis, suggesting that the p53/CTGF pathway may be a therapeutic target in the treatment of liver fibrosis.

Authors

Takahiro Kodama, Tetsuo Takehara, Hayato Hikita, Satoshi Shimizu, Minoru Shigekawa, Hinako Tsunematsu, Wei Li, Takuya Miyagi, Atsushi Hosui, Tomohide Tatsumi, Hisashi Ishida, Tatsuya Kanto, Naoki Hiramatsu, Satoshi Kubota, Masaharu Takigawa, Yoshito Tomimaru, Akira Tomokuni, Hiroaki Nagano, Yuichiro Doki, Masaki Mori, Norio Hayashi

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Figure 1

Hepatocyte-specific Mdm2-knockout mice show endogenous p53 accumulation, leading to transactivation of p53-regulated genes.

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Hepatocyte-specific Mdm2-knockout mice show endogenous p53 accumulation,...
(A–F) Mdm2fl/flalb-cre [Cre(+)] mice and Mdm2fl/fl [Cre(–)] mice were analyzed at 6 weeks of age. (A) p53 mRNA levels in the liver tissue were determined by real-time RT-PCR; 7 mice per group. (B) Expression of p53 protein in liver tissue was assessed by Western blot analysis. (C) Expression of p53 protein in isolated hepatocytes upon treatment with 20 μM nutlin-3a or vehicle was assessed by Western blot analysis. (D) Expression of p53 protein in the liver section was determined by immunohistochemical analysis. Original magnification, ×200. (E) p21, Noxa, Bax, and Puma mRNA levels in isolated hepatocytes and NPCs were determined by real-time RT-PCR; 4 mice per group. Expression of p21, Noxa, Bax, and Puma proteins in liver tissue was assessed by Western blot analysis (F).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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