Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human immunodeficiency virus type 1 (HIV-1) can establish latent infection following provirus integration into the host genome. NF-kappaB plays a critical role in activation of HIV-1 gene expression by cytokines and other stimuli, but the signal transduction pathways that regulate the switch from latent to productive infection have not been defined. Here, we show that ERK1/ERK2 mitogen-activated protein kinase (MAPK) plays a central role in linking signals at the cell surface to activation of HIV-1 gene expression in latently infected cells. MAPK was activated by cytokines and phorbol 12-myristate 13-acetate in latently infected U1 cells. The induction of HIV-1 expression by these stimuli was inhibited by PD98059 and U0126, which are specific inhibitors of MAPK activation. Studies using constitutively active MEK or Raf kinase mutants demonstrated that MAPK activates the HIV-1 long terminal repeat (LTR) through the NF-kappaB sites. Most HIV-1 inducers activated NF-kappaB via a MAPK-independent pathway, indicating that activation of NF-kappaB is not sufficient to explain the activation of HIV-1 gene expression by MAPK. In contrast, all of the stimuli activated AP-1 via a MAPK-dependent pathway. NF-kappaB and AP-1 components c-Fos and c-Jun were shown to physically associate by yeast two-hybrid assays and electrophoretic mobility shift assays. Coexpression of NF-kappaB and c-Fos or c-Jun synergistically transactivated the HIV-1 LTR through the NF-kappaB sites. These studies suggest that MAPK acts by stimulating AP-1 and a subsequent physical and functional interaction of AP-1 with NF-kappaB, resulting in a complex that synergistically transactivates the HIV-1 LTR. These results define a mechanism for signal-dependent activation of HIV-1 replication in latently infected cells and suggest potential therapeutic strategies for unmasking latent reservoirs of HIV-1.
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PMID:ERK MAP kinase links cytokine signals to activation of latent HIV-1 infection by stimulating a cooperative interaction of AP-1 and NF-kappaB. 1048 48

Human immunodeficiency virus type-1 (HIV-1) gene expression is known to be affected by numerous cytokines or growth factors. However, the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on long terminal repeat (LTR)-mediated transcription of HIV-1 still remains unknown. By transient transfection experiments with HIV-1 LTR reporter constructs, we showed that strong LTR-mediated activation was induced by GM-CSF in mouse Ba/F3 cells expressing human GM-CSF receptors (GM-CSFR). Mutational analysis of the HIV-1 LTR reporters revealed that both NF-kappaB and Sp1 binding sites play important roles as positive regulatory elements. Analysis of various mutants of the cytoplasmic region of GM-CSFR indicated that both the conserved membrane proximal region and tyrosine residues located in the distal part of the beta subunit were required for HIV-1 LTR activation. Possible involvement of MAPK and PI3-K signalling pathways was suggested by the partial inhibition by wortmannin, a specific inhibitor of the PI3-K pathway, and enhancement by constitutively active MEK1, of HIV-1 LTR activation. However, the MEK1 pathway is not essential since MEK1 inhibitor PD98059 did not suppress GM-CSF-induced HIV-1-LTR activation. Further analyses of GM-CSFR mutants suggested that some other unknown signalling pathway also participates in GM-CSF-induced HIV-1 LTR activation. Taken together, the data suggest that GM-CSF could upregulate the LTR-driven transcription of HIV-1 through modulation of NF-kappaB and SP1 by multiple signalling pathways.
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PMID:Human GM-CSF induces HIV-1 LTR by multiple signalling pathways. 1245 35