Document Detail


Met acts through Abl to regulate p53 transcriptional outcomes and cell survival in the developing liver.
MedLine Citation:
PMID:  22889954     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 S(389), 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.
Authors:
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
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-08-10
Journal Detail:
Title:  Journal of hepatology     Volume:  57     ISSN:  1600-0641     ISO Abbreviation:  J. Hepatol.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-19     Completed Date:  2013-06-21     Revised Date:  2013-12-05    
Medline Journal Info:
Nlm Unique ID:  8503886     Medline TA:  J Hepatol     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  1292-8     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Survival
Cyclin-Dependent Kinase Inhibitor p21 / genetics
Hepatocytes / physiology*
Liver / embryology*
Mice
Phosphorylation
Proto-Oncogene Proteins c-abl / physiology*
Proto-Oncogene Proteins c-bcl-2 / genetics
Proto-Oncogene Proteins c-mdm2 / genetics
Proto-Oncogene Proteins c-met / physiology*
Transcription, Genetic*
Tumor Suppressor Protein p53 / physiology*
p38 Mitogen-Activated Protein Kinases / metabolism
Grant Support
ID/Acronym/Agency:
R01 CA133346/CA/NCI NIH HHS; R01 GM100411/GM/NIGMS NIH HHS; R01 NS039475/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Cyclin-Dependent Kinase Inhibitor p21; 0/Pmaip1 protein, mouse; 0/Proto-Oncogene Proteins c-bcl-2; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53; EC 2.7.10.1/Proto-Oncogene Proteins c-met; EC 2.7.10.2/Proto-Oncogene Proteins c-abl; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases; EC 6.3.2.19/Proto-Oncogene Proteins c-mdm2
Comments/Corrections

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