Multiple neurotoxic stresses converge on MDMX proteolysis to cause neuronal apoptosis.
MDMX has been shown to modulate p53 in dividing cells after DNA damage. In this study, we investigated the role of MDMX in primary cultures of neurons undergoing cell death. We found that DNA damage, but also membrane-initiated apoptotic stresses (glutamate receptor; Amyloid beta precursor) or survival factor deprivation downregulated MDMX protein levels. Forced downregulation of murine double minute X (MDMX) by shRNA induced apoptosis suggesting that MDMX is required for survival in neurons. Protease inhibitors prevented the loss of MDMX after neurotoxic treatments, indicating a regulation of protein stability. Some, but not all, neurotoxic stresses induced phosphorylation of MDMX at serine 367, further supporting regulation at the protein level. Interestingly, we found that depending on the stimulus either p53 or E2F1 was induced, but overexpression of MDMX inhibited the transcriptional activity of both proapoptotic factors, and maintained neuronal viability upon neurotoxic stresses. Taken together, our data show that MDMX is an antiapoptotic factor in neurons, whose degradation is induced by various stresses and allows activation of p53 and E2F-1 during neuronal apoptosis.
Benosman
S
S
INSERM U692, Laboratoire de Signalisations Moléculaires et Neurodégénérescence, Université Louis Pasteur, Faculté de Médecine, UMRS692, Strasbourg, France.
Gross
I
I
Clarke
N
N
Jochemsen
A G
AG
Okamoto
K
K
Loeffler
J-P
JP
Gaiddon
C
C
D016564:Amyloid beta-Protein Precursor / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects; D050687:E2F1 Transcription Factor / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020868:Gene Silencing / Q000187:drug effects; D051379:Mice; D009474:Neurons / Q000166:cytology* / Q000187:drug effects*; D009498:Neurotoxins / Q000633:toxicity*; D061988:Proteasome Inhibitors; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism