Met acts through Abl to regulate p53 transcriptional outcomes and cell survival in the developing liver

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• 作者：Alessandro Furlan¹ ; ^&dagger ; ; Fabienne Lamballe¹ ; ^&dagger ; ; Venturina Stagni² ; Azeemudeen Hussain¹ ; Sylvie Richelme¹ ; Andrea Prodosmo³ ; Anice Moumen¹ ; Christine Brun⁴ ; Ivan del Barco Barrantes⁵ ; ⁶ ; J. Simon C. Arthur⁷ ; Anthony J. Koleske⁸ ; Angel R. Nebreda⁵ ; ⁶ ; Daniela Barilà ; ² ; Flavio Maina¹ ; ^{flavio.maina@ibdml.univmed.fr} ; ^{flavio.maina@univ-amu.fr}
• 关键词：RTKs ; receptor tyrosine kinases ; HGF ; hepatocyte growth factor ; 5FU ; 5-fluoro-uracile ; RU ; relative units ; ActD ; actinomycinD ; AU ; arbitrary units
• 刊名：Journal of Hepatology
• 出版年：2012
• 出版时间：December, 2012
• 年：2012
• 卷：57
• 期：6
• 页码：1292-1298
• 全文大小：1085 K

文摘

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Background & Aims

Genetic studies indicate that distinct signaling modulators are each necessary but not individually sufficient for embryonic hepatocyte survival <em>in vivoem>. Nevertheless, how signaling players are interconnected into functional circuits and how they coordinate the balance of cell survival and death in developing livers are still major unresolved issues. In the present study, we examined the modulation of the p53 pathway by HGF/Met in embryonic livers.

Methods

We combined pharmacological and genetic approaches to biochemically and functionally evaluate p53 pathway modulation in primary embryonic hepatocytes and in developing livers. RT-PCR arrays were applied to investigate the selectivity of p53 transcriptional response triggered by Met.

Results

Met recruits p53 to regulate the liver developmental program, by qualitatively modulating its transcriptional properties: turning on the <em>Mdm2em> survival gene, while keeping death and cell-cycle arrest genes <em>Pmaip1em> and <em>p21em> silent. We investigated the mechanism leading to p53 regulation by Met and found that Abl and p38MAPK are required for p53 phosphorylation on S³⁸⁹, Mdm2 upregulation, and hepatocyte survival. Alteration of this signaling mechanism switches p53 properties, leading to p53-dependent cell death in embryonic livers. RT-PCR array studies affirmed the ability of the Met-Abl-p53 axis to modulate the expression of distinct genes that can be regulated by p53.

Conclusions

A signaling circuit involving Abl and p38MAPK is required downstream of Met for the survival of embryonic hepatocytes, via qualitative regulation of the p53 transcriptional response, by switching its proapoptotic into survival properties.