Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human immunodeficiency virus type 1 (HIV-1) uses the chemokine receptors CCR5 and CXCR4 for entry. Macrophages and microglia (M/M) are the principal productively infected brain cells in HIV encephalopathy (HIVE), and neuronal injury is believed to result both from direct effects of viral proteins and indirect effects mediated by macrophage activation and secretion of neurotoxic products. In vitro, direct injury by the viral envelope glycoprotein gp120 can be mediated by neuronal CXCR4, but most HIV-1 isolates from the central nervous system (CNS) studied to date use CCR5 (R5 strains) rather than CXCR4 (X4 or R5X4 strains). Additionally, it remains unknown how HIV induces M/M activation and neurotoxin secretion. To address these issues, the authors analyzed a CNS-derived primary isolate, TYBE, and showed that it uses CXCR4 only and replicates efficiently in macrophages through CXCR4-mediated entry. The authors also showed that both R5 and X4 gp120 activate intracellular signals in macrophages through CCR5 and CXCR4, including calcium elevations; K+, Cl- and nonselective cation channel activation; phosphorylation of the nonreceptor tyrosine kinase Pyk2; and activation of p38 and SAPK/JNK mitogen-activated protein kinases (MAPKs). Finally, the authors showed that macrophages stimulated with gp120 produce soluble factors through MAPK-dependent pathways, including beta-chemokines implicated in HIVE pathogenesis. The findings emphasize that both X4 and R5 HIV-1 isolates may contribute to HIVE pathogenesis, and that gp120/chemokine receptor interactions in M/M trigger specific signal transduction pathways that may affect M/M function and provide a mechanism underlying CNS injury.
 ...
PMID:Chemokine receptor utilization and macrophage signaling by human immunodeficiency virus type 1 gp120: Implications for neuropathogenesis. 1498 45

Human immunodeficiency virus type 1 (HIV-1) establishes a persistent, nonproductive state within a small population of memory CD4(+) cells. The transcription factor LSF binds to sequences within the HIV-1 long terminal repeat (LTR) initiation region and recruits a second factor, YY1, to the LTR. These factors then cooperatively recruit histone deacetylase 1 to the LTR, resulting in inhibition of transcription. This appears to be one mechanism contributing to HIV persistence within resting CD4(+) T cells. We sought to further detail LSF binding to the HIV-1 LTR and factors that regulate LSF occupancy. We find that LSF binds the LTR as a tetramer and that binding is regulated by phosphorylation mediated by mitogen-activated protein kinases (MAPKs). In vitro, phosphorylation of LSF by Erk decreases binding to the LTR, while binding is increased by p38 phosphorylation. LSF occupancy at LTR chromatin is increased by the p38 agonist anisomycin and decreased by specific p38 inhibition. p38 inhibition also results in increased acetylation of histone H4 at the LTR nucleosome adjacent to the LSF binding site. p38 inhibition also blocked the ability of YY1 to inhibit activation of the integrated HIV promoter. Finally, HIV was recovered from the resting CD4(+) T cells of aviremic, HIV-infected donors upon treatment of these cells with specific inhibitor of p38. These data suggest that the MAPK pathway regulates LSF binding to the LTR and thereby one aspect of the regulation of HIV expression. This mechanism could be exploited as a novel therapeutic target to disrupt latent HIV infection.
 ...
PMID:Mitogen-activated protein kinases regulate LSF occupancy at the human immunodeficiency virus type 1 promoter. 1585 81

Human immunodeficiency virus type 1 (HIV-1) infection is initiated by binding of the viral envelope glycoprotein gp120 to CD4 followed by a chemokine receptor, but these interactions may also take place independently from infection. gp120 stimulation of primary human macrophages is known to trigger production of cytokines implicated in pathogenesis, particularly tumor necrosis factor alpha (TNF-alpha), but the mechanisms have not been determined. We sought to define the pathways responsible for TNF-alpha secretion by monocyte-derived macrophages (MDM) following HIV-1 gp120 stimulation. MDM exposure to recombinant macrophage-tropic (R5) gp120 led to dose- and donor-dependent release of TNF-alpha, which was cyclohexamide-sensitive and associated with up-regulated message. Pretreatment with specific inhibitors of the mitogen-activated protein kinases (MAPK) extracellular signal-regulated kinase 1/2 (ERK-1/2; PD98059, U0126) and p38 (SB202190, PD169316) inhibited the secretion of TNF-alpha. gp120-elicited TNF-alpha production was also blocked by phosphatidylinositol-3 kinase (PI-3K) inhibitors (wortmannin, LY294002). Moreover, PI-3K inhibition ablated gp120-induced phosphorylation of p38 and ERK-1/2. The response was inhibited by a CC chemokine receptor 5 (CCR5)-specific antagonist, indicating that CCR5 was in large part responsible. These results indicate that gp120-elicited TNF-alpha production by macrophages involves chemokine receptor-mediated PI-3K and MAPK activation, that PI-3K is an upstream regulator of MAPK in this pathway, and that p38 and ERK-1/2 independently regulate TNF-alpha production. These gp120-triggered signaling pathways may be responsible for inappropriate production of proinflammatory cytokines by macrophages, which are believed to play a role in immunopathogenesis and in neurological sequelae of AIDS.
 ...
PMID:HIV-1 gp120-induced TNF-{alpha} production by primary human macrophages is mediated by phosphatidylinositol-3 (PI-3) kinase and mitogen-activated protein (MAP) kinase pathways. 1608 99