Human cytomegalovirus induces drug resistance and alteration of programmed cell death by accumulation of deltaN-p73alpha.
Intrauterine transmission of human cytomegalovirus (HCMV) to the fetus following primary infection in early and late pregnancy usually results in severe neurological handicaps and sensorineural hearing loss with typical migrational anomalies, optic atrophy, disturbed myelination, cerebella hypoplasia, microcephaly, hydrocephaly, and lissencephaly. Recently, evidences raised from the phenotype of p73-deficient mice show that an association may exist between the expression of the TP53 homologous gene and HCMV tropism in the brain, suggesting an implication of p73 in viral persistence. In this study, we demonstrated that HCMV-mediated inhibition of apoptosis only occurs in p73-expressing cells. Upon infection, an accumulation of deltaN-p73alpha isoforms was observed in HCMV-infected p73-positive cells. This phenomenon was shown to be responsible for the subsequent acquired resistance to apoptosis of infected cells. Inhibition of apoptosis in p73-positive cells by HCMV may thus contribute both to virus persistency and abnormal nervous cell survival. This finding provides the first molecular basis for HCMV-associated abnormal embryonic development and neurological defects in newborns.
Allart
Sophie
S
INSERM U395, CHU Purpan, BP3028, 31024, Toulouse Cédex, France.
Martin
Helene
H
Detraves
Claire
C
Terrasson
Jerome
J
Caput
Daniel
D
Davrinche
Christian
C
D017209:Apoptosis; D015153:Blotting, Western; D002460:Cell Line; D002465:Cell Movement; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology; D003587:Cytomegalovirus / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D024882:Drug Resistance, Viral; D016147:Genes, Tumor Suppressor; D006801:Humans; D008856:Microscopy, Fluorescence; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D002945:Cisplatin