HIV-1 Nef promotes survival of TF-1 macrophages by inducing Bcl-XL expression in an extracellular signal-regulated kinase-dependent manner.
The Nef protein of human immunodeficiency virus-1 (HIV-1) is essential for the progression from human and simian immunodeficiency virus infection to full-blown AIDS. Recent studies indicate that Nef generates anti-apoptotic signals in HIV-infected T cells, suppressing cell death early in infection to allow productive viral replication. Previous work from our laboratory has shown that Nef also promotes proliferation of myeloid cells through a signal transducer and activator of transcription 3-dependent pathway. Here we demonstrate that Nef suppresses cell death induced by cytokine deprivation in the human macrophage precursor cell line, TF-1. Nef selectively induced up-regulation of Bcl-XL, an anti-apoptotic gene that is also regulated by granulocyte/macrophage-colony stimulating factor in this cell line. Activation of the extracellular signal-regulated kinase (Erk) mitogen-activated protein kinase pathway also correlated with the survival of TF-1/Nef cells. Using the selective mitogen-activated protein kinase kinase inhibitor PD98059, we found that Nef-induced Erk signaling is essential for Bcl-XL up-regulation and cell survival. In contrast, expression of Bcl-XL and TF-1 survival was not affected by dominant-negative signal transducer and activator of transcription 3. These data suggest that Nef produces survival signals in myeloid cells through Erk-mediated Bcl-XL induction, a pathway distinct from Nef survival pathways recently reported in T lymphocytes.
Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
Hyun-Jung
HJ
Choi
Thomas E
TE
Smithgall
D017209:Apoptosis; D015153:Blotting, Western; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival; D002867:Chromones / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D019281:Dimerization; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015693:Gene Products, nef / Q000378:metabolism / Q000502:physiology*; D005799:Genes, Dominant; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism / Q000821:virology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D012313:RNA / Q000378:metabolism; D012260:Ribonucleases / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D015854:Up-Regulation; D014779:Virus Replication; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D002867:Chromones; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D015693:Gene Products, nef; D009025:Morpholines; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D051020:bcl-X Protein; D049452:Green Fluorescent Proteins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D012313:RNA; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D048052:Mitogen-Activated Protein Kinase 3; D012260:Ribonucleases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one