Visit our Expo - Redox and Inflammation signaling 2012

Session XII : Cell death and neurodegenerative diseases Poster XII, 1
MDMX is a Critical Regulator of Neuronal Apoptosis induced by APP Stimulat Session
Samir Benosman1, Koji Okamoto2, Christian Gaiddon3 and Jean-Philippe Loeffler4
1,3,4 INSERM U692, School of Medicine, Louis Pasteur University; 11 Humann St.,
Strasbourg, France.
2 National Cancer Center; Tokyo, Japan
Emails: 1 benosmans@neurochem.u-strasbg.fr ; 3 gaiddon@neurochem.u-strasbg.fr ;
4 loeffler@neurochem.u-strasbg.fr
MDMX is an analogue of MDM2 that has been shown to modulate p53 function in various
cell lines. In the case of neurons, data regarding the implication of MDMX in the p53
apoptotic pathway are still lacking. We investigated the role of MDMX in primary immature
and mature Cerebellar Granule Neurons undergoing different stresses leading to cell death. To
that aim, we used DNA damaging agents including Neocarzinostatin (NCS) and Cisplatin
(CIS), and neuron-specific stresses such as low K+ (LK) and APP stimulation. In All
conditions we obtained a caspase-activating apoptosis. p53 protein was stabilized in all
conditions except LK. Furthermore, apoptosis caused by DNA damage, but not by LK, was
suppressed by the dominant-negative mutant of p53, indicating that cell death caused by LK
is p53-independent. In contrast, E2F-1, another pro-apoptotic factor known to interact with
MDMX, was stabilized in response to LK and poorly in the remaining conditions.
Concomitantly, MDMX protein levels decreased in all conditions, LK included. The loss of
MDMX was not due to transcriptional repression since MDMX mRNA levels remained stable
in the former conditions. On the other hand, protease inhibitors reversed the loss of MDMX
suggesting a regulation of protein stability during neuronal insults. Furthermore, overexpression
of MDMX inhibited the transcriptional activity of both p53 and E2F-1, and
partially restored neuronal viability following apoptotic treatments. Taken together, our data
show that MDMX is an antiapoptotic factor in neurons in which MDMX degradation is
induced by multiple stress signals, allowing activation of p53 and E2F-1 during neuronal
apoptosis.
Supported by Association Francaise contre les Myopathies (AFM) and Association pour la
Recherche sur le Cancer (ARC)
- 459 -