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

Alessandro Furlan, Fabienne Lamballe, Venturina Stagni, Azeemudeen Hussain, Sylvie Richelme, Andrea Prodosmo, Anice Moumen, Christine Brun, Ivan Del Barco Barrantes, J. Simon C. Arthur, Anthony J. Koleske, Angel R. Nebreda, Daniela Barilà, Flavio Maina (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    17 Citations (Scopus)


    Background & Aims: Genetic studies indicate that distinct signaling modulators are each necessary but not individually sufficient for embryonic hepatocyte survival in vivo. 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 Mdm2 survival gene, while keeping death and cell-cycle arrest genes Pmaip1 and p21 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.

    Original languageEnglish
    Pages (from-to)1292-1298
    Number of pages7
    JournalJournal of Hepatology
    Issue number6
    Publication statusPublished - 1 Dec 2012


    • Abl
    • Cell survival
    • Embryonic hepatocytes
    • HGF/Met
    • p53 Signaling
    • RTK signaling in vivo

    ASJC Scopus subject areas

    • Hepatology


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