Activation of JNK-dependent pathway is required for HIV viral protein R-induced apoptosis in human monocytic cells: involvement of antiapoptotic BCL2 and c-IAP1 genes.
Human immunodeficiency virus (HIV) accessory protein viral protein R (Vpr) plays a key role in virus replication and induces cell cycle arrest and apoptosis in various cell types including T cells and neuronal and tumor cells following infection with Vpr-expressing HIV isolates or exposure to the extracellular Vpr protein. The C-terminal Vpr peptide encompassing amino acids 52-96 (Vpr-(52-96)) is required for exerting the apoptotic effects, whereas the N-terminal Vpr-(1-45) peptide is responsible for virus transcription. We demonstrate that Vpr-(52-96) induced apoptosis in human promonocytic THP-1 cells and primary monocytes through the mitochondrial pathway in a caspase-dependent manner. To understand the regulation of Vpr-induced apoptosis, we investigated the signaling pathways, particularly the MAPKs, and the transcription factors involved. Although both Vpr-(52-96) and Vpr-(1-45) peptides induced phosphorylation of all the three members of the MAPKs, Vpr-(52-96)-activated JNK selectively induced apoptosis in monocytic cells through the mitochondrial pathway as determined by using JNK inhibitors SP60025, dexamethasone, curcumin, and JNK-specific small interfering RNAs. Furthermore Vpr-(52-96)-induced apoptosis was mediated by inhibition of downstream antiapoptotic Bcl2 and c-IAP1 genes whose expression could be restored following pretreatment with JNK-specific inhibitors. Overall the results suggest that Vpr-(52-96)-activated JNK plays a key role in inducing apoptosis through the down-regulation of antiapoptotic Bcl2 and c-IAP1 genes.
Mishra
Sasmita
S
Biochemistry, Microbiology, and Immunology, University of Ottawa K1H 8M5 and Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H 8L1, Canada.
Mishra
Jyoti P
JP
Biochemistry, Microbiology, and Immunology, University of Ottawa K1H 8M5 and Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H 8L1, Canada.
Kumar
Ashok
A
Biochemistry, Microbiology, and Immunology, University of Ottawa K1H 8M5 and Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H 8L1, Canada; Pathology and Laboratory Medicine and Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H 8L1, Canada; Departments of Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H 8L1, Canada; Infectious Disease and Vaccine Research Centre, Research Institute, Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H 8L1, Canada. Electronic address: akumar@uottawa.ca.
D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D015536:Down-Regulation; D016336:Gene Products, vpr / Q000235:genetics / Q000378:metabolism*; D006678:HIV / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism; D009000:Monocytes / Q000201:enzymology* / Q000821:virology; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology; D014158:Transcription, Genetic; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology; D054325:vpr Gene Products, Human Immunodeficiency Virus
D016336:Gene Products, vpr; D051034:Inhibitor of Apoptosis Proteins; D010455:Peptides; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D054325:vpr Gene Products, Human Immunodeficiency Virus; D048670:MAP Kinase Kinase 4; D020169:Caspases