Met acts through Abl to regulate p53 transcriptional outcomes and cell survival in the developing liver.
OBJECTIVE
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.
Aix-Marseille Univ, IBDML, CNRS UMR 7288, Marseille, France.
Alessandro
A
Furlan
Fabienne
F
Lamballe
Venturina
V
Stagni
Azeemudeen
A
Hussain
Sylvie
S
Richelme
Andrea
A
Prodosmo
Anice
A
Moumen
Christine
C
Brun
Ivan
I
Del Barco Barrantes
J Simon C
JS
Arthur
Anthony J
AJ
Koleske
Angel R
AR
Nebreda
Daniela
D
Barilà
Flavio
F
Maina
D000818:Animals; D002470:Cell Survival; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D022781:Hepatocytes / Q000502:physiology*; D008099:Liver / Q000196:embryology*; D051379:Mice; D010766:Phosphorylation; D016315:Proto-Oncogene Proteins c-abl / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; C408009:Pmaip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2; D019859:Proto-Oncogene Proteins c-met; D016315:Proto-Oncogene Proteins c-abl; D048051:p38 Mitogen-Activated Protein Kinases