The human herpes virus 8-encoded viral FLICE inhibitory protein protects against growth factor withdrawal-induced apoptosis via NF-kappa B activation.
The human herpes virus 8 (HHV8)-encoded viral FLICE (Fas-associating protein with death domain-like interleukin-1-converting enzyme) inhibitory protein (vFLIP) is believed to protect cells against death receptor-mediated apoptosis. In the present study we demonstrate that expression of HHV8 vFLIP in a growth factor-dependent TF-1 leukemia cell line protects against growth factor withdrawal-induced apoptosis. Unlike vector-expressing cells, those expressing HHV8 vFLIP maintain their mitochondrial membrane potential upon withdrawal from growth factor and also exhibit a block in the activation of caspases. The protective effect of HHV8 vFLIP is associated with its ability to activate the nuclear factor-kappa B (NF-kappaB) pathway and is missing in the vFLIP encoded by equine herpes virus 2 that lacks this activity. Inhibition of the NF-kappaB pathway by IkappaB superrepressor, lactacystin, MG132, arsenic trioxide, and phenylarsine oxide reverse the protection against growth factor withdrawal-induced apoptosis conferred by HHV8 vFLIP. HHV8 vFLIP up-regulates the expression of Bcl-x(L), an antiapoptotic member of the Bcl2 family, which is a known target of the NF-kappaB pathway. Collectively, the above results suggest that HHV8 vFLIP-induced NF-kappaB activation may contribute to cellular transformation seen in association with HHV8 infection by preventing the apoptosis of cells destined to die because of growth factor deprivation.
Sun
Qinmiao
Q
Hamon Center for Therapeutic Oncology Research and Division of Hematology-Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA.
Matta
Hittu
H
Chaudhary
Preet M
PM
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000208:Acute Disease; D017209:Apoptosis / Q000502:physiology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D002472:Cell Transformation, Viral / Q000235:genetics; D004789:Enzyme Activation; D015967:Gene Expression Regulation, Viral; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D020672:I-kappa B Proteins / Q000502:physiology; D007951:Leukemia, Myeloid / Q000473:pathology; D007976:Leupeptins / Q000494:pharmacology; D008928:Mitochondria / Q000502:physiology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D010087:Oxides / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D018144:Rhadinovirus / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology*; D051020:bcl-X Protein
D001152:Arsenicals; C494811:BCL2L1 protein, human; D020672:I-kappa B Proteins; D007976:Leupeptins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D009363:Neoplasm Proteins; D010087:Oxides; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D051020:bcl-X Protein; C029341:oxophenylarsine; C067713:lactacystin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000077237:Arsenic Trioxide; D000111:Acetylcysteine