1. Involvement of extracellular signal-regulated kinase module in HIV-mediated CD4 signals controlling activation of nuclear factor-kappa B and AP-1 transcription factors.
- Author
-
Briant L, Robert-Hebmann V, Sivan V, Brunet A, Pouysségur J, and Devaux C
- Subjects
- Apoptosis immunology, Biological Transport immunology, CD4 Antigens metabolism, Calcium-Calmodulin-Dependent Protein Kinases antagonists & inhibitors, Calcium-Calmodulin-Dependent Protein Kinases biosynthesis, Calcium-Calmodulin-Dependent Protein Kinases genetics, Epitopes immunology, HIV-1 metabolism, HIV-1 physiology, Hemagglutinin Glycoproteins, Influenza Virus immunology, Humans, MAP Kinase Kinase 1, Mutagenesis, Site-Directed, Protein Binding immunology, Protein Serine-Threonine Kinases biosynthesis, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases physiology, Protein-Tyrosine Kinases biosynthesis, Protein-Tyrosine Kinases genetics, Protein-Tyrosine Kinases physiology, Signal Transduction immunology, T-Lymphocytes enzymology, T-Lymphocytes immunology, T-Lymphocytes metabolism, Tumor Cells, Cultured, Virus Replication immunology, CD4 Antigens physiology, Calcium-Calmodulin-Dependent Protein Kinases physiology, HIV-1 immunology, Mitogen-Activated Protein Kinase Kinases, NF-kappa B metabolism, Transcription Factor AP-1 metabolism
- Abstract
Although the molecular mechanisms by which the HIV-1 triggers either T cell activation, anergy, or apoptosis remain poorly understood, it is well established that the interaction of HIV-1 envelope glycoproteins with cell surface CD4 delivers signals to the target cell, resulting in activation of transcription factors such as NF-kappa B and AP-1. In this study, we report the first evidence indicating that kinases MEK-1 (MAP kinase/Erk kinase) and ERK-1 (extracellular signal-regulated kinase) act as intermediates in the cascade of events that regulate NF-kappa B and AP-1 activation upon HIV-1 binding to cell surface CD4. We found that CEM cells transfected with dominant negative forms of MEK-1 or ERK-1 do not display NF-kappa B activation after HIV-1 binding to CD4. In contrast, NF-kappa B activation was observed in these cells after PMA stimulation. Although the different cell lines studied expressed similar amounts of CD4 and p56(lck), HIV-1 replication and HIV-1-induced apoptosis were slightly delayed in cells expressing dominant negative forms of MEK-1 or ERK-1 compared with parental CEM cells and cells expressing a constitutively active mutant form of MEK-1 or wild-type ERK-1. In light of recently published data, we propose that a positive signal initiated following oligomerization of CD4 by the virus is likely to involve a recruitment of active forms of p56(lck), Raf-1, MEK-1, and ERK-1, before AP-1 and NF-kappa B activation.
- Published
- 1998