The expression of a new variant of the pro-apoptotic molecule Bax, Baxpsi, is correlated with an increased survival of glioblastoma multiforme patients.
Pro- and anti-apoptotic members of the BCL-2 family play a central role in the implementation of apoptosis. Bax, a pro-apoptotic member of this family, has as such been considered as a potential tumor suppressor. Here, we have examined the expression of Bax in 55 patients with glioblastoma multiforme (GBM), the most common and aggressive form of brain tumors. We report on the existence of a new form of Bax, present in 24% of the patients, which we called Baxpsi. Baxpsi is a N-terminal truncated form of Bax which results from a partial deletion of the exon 1 of Bax gene. Baxpsi and the wild-type form, Baxalpha, are encoded by distinct mRNAs, both of which are present in normal tissues. Glial tumors express either Baxalpha or Baxpsi proteins, an apparent consequence of an exclusive transcription of the corresponding mRNAs. The latter feature could be partially linked to distinct methylation profiles of Bax gene in these tumors. The Baxpsi protein is preferentially localized to mitochondria and is a more powerful inducer of apoptosis than Baxalpha. Baxpsi tumors exhibit a slow proliferation in Swiss nude mice and this feature can be circumvented by the co-expression of the Bcl-2 transgene, the functional antagonist of Bax. More importantly, the expression of Baxpsi correlates with a longer survival in patients (18 months versus 10 months for Baxalpha patients). Thus, our results provide the first indication of a beneficial involvement of a variant of the pro-apoptotic protein Bax in tumor progression.
Cartron
Pierre-François
PF
IFR 26, INSERM UMR 419, 9 quai Moncousu, 44035 Nantes Cedex 01, France.
Oliver
Lisa
L
Martin
Stéphane
S
Moreau
Carole
C
LeCabellec
Marie-Thérèse
MT
Jezequel
Pascal
P
Meflah
Khaled
K
Vallette
François M
FM
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D015152:Blotting, Northern; D015139:Blotting, Southern; D001932:Brain Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D005909:Glioblastoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D015996:Survival Rate; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D051028:bcl-2-Associated X Protein