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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / immunology
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Biological Transport / immunology
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CD4 Antigens / metabolism
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CD4 Antigens / physiology*
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Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
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Calcium-Calmodulin-Dependent Protein Kinases / biosynthesis
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Calcium-Calmodulin-Dependent Protein Kinases / genetics
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Calcium-Calmodulin-Dependent Protein Kinases / physiology*
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Epitopes / immunology
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HIV-1 / immunology*
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HIV-1 / metabolism
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HIV-1 / physiology
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Hemagglutinin Glycoproteins, Influenza Virus / immunology
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Humans
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MAP Kinase Kinase 1
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Mitogen-Activated Protein Kinase Kinases*
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Mutagenesis, Site-Directed
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NF-kappa B / metabolism*
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Protein Binding / immunology
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Protein Serine-Threonine Kinases / biosynthesis
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / physiology
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Protein-Tyrosine Kinases / biosynthesis
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / physiology
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Signal Transduction / immunology
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T-Lymphocytes / enzymology
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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Transcription Factor AP-1 / metabolism*
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Tumor Cells, Cultured
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Virus Replication / immunology
Substances
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CD4 Antigens
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Epitopes
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Hemagglutinin Glycoproteins, Influenza Virus
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NF-kappa B
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Transcription Factor AP-1
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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MAP Kinase Kinase 1
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MAP2K1 protein, human
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Mitogen-Activated Protein Kinase Kinases