Visit our Expo - Redox and Inflammation signaling 2012

Session X : Cell death in cancer Poster X, 74
HGF supports embryonic hepatocyte survival by suppressing apoptotic pathways
involving p53 and TNFalpha/FasL
Anice Moumen1, Alessandro Ieraci1 and Flavio Maina1
1IBDML, Campus de Luminy-Case 907, 13288 Marseille Cedex 09, France - 2Dpto.
Bioquimica y Biologia Molecular II, Facultad de Farmacia, Universidad Complutense,
Ciudad Universitaria, 28040 Madrid, Spain.
E-mail: moumen@ibdm.univ-mrs.fr
Survival of embryonic hepatocytes is controlled by a number of anti- and pro-apoptotic
signals. To date, the only ligand/receptor couple known to induce hepatocyte survival in vivo
is HGF and its cognate receptor tyrosine kinase Met. However, their downstream effectors
involved in this process remain to be elucidated. We previously showed that met specificityswitch
mutants are not able to mediate hepatocyte survival, thus resulting in massive
apoptosis in developing livers as observed in met loss-of-function mutants. Taking advantage
of the incomplete signalling of these mutant receptors, we asked which combination of
signalling effectors is sufficient for proper hepatocyte survival. We found that Met makes use
of distinct networks involving Flip and Mdm2 to block the pro-apoptotic signals TNF/FasL
and p53, respectively. In contrast, modulators of cell survival such as CREB, Gab1 and Jun,
are not sufficient. Thus, our results clearly show that during liver development, Met controls
hepatocyte survival by modulating the cross-talk of pro- and anti-apoptotic signals.
Furthermore, our use of defined mouse signalling mutants resolves some of the complexity
underlying the mechanisms that regulate the survival of hepatocytes and their susceptibility to
apoptotic signals.
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