Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0268596 (EMA)
 2,520 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stimulation of macrophages by a variety of agents causes activation of mitogen-activated protein kinases (MAPKs). Activation of MAPKs by lipopolysaccharide involves CD14 and Toll receptors. Subsequent steps still remain to be explored. Tumor necrosis factor-alpha (TNF-alpha)-induced activation of MAPKs has been shown to involve the death domain proteins (TRADD, FADD, MADD) and TRAFs. Other molecules involved in this pathway include the protein kinases, ASK1, germinal center kinase (GCK), hematopoietic progenitor kinase 1 (HPK1), and GCK-related kinase (GCKR). Although, these pathways have been described in various cell types, their role in macrophages remains to be established. The availability of knockout mice and constitutively active and dominant-negative mutants of MAPKs should greatly enhance our understanding of this field. The activation of MAPKs seems to be different in cell lines compared with primary cells. Among the macrophages, cells from different compartments show different expression of receptors and signal transduction molecules. These differences may account for differences in MAPK activation and other phenotypic differences in macrophages from different compartments. Therefore, it is important to use primary cells for studying MAPK signal-transduction pathways, and the data from cell lines should not be extrapolated to primary cells.
 ...
PMID:MAP kinase activation in macrophages. 1120 64

Tumor necrosis factor (TNF) alpha and mitogen-activated protein kinase/c-Jun N-terminal kinase (MAPK/JNK) pathways are both implicated in Alzheimer's disease (AD) pathogenesis. Increased expression of several members of the TNF pathway and JNK activation of c-Jun ultimately result in neuronal apoptosis. DENN/MADD, a multifunctional domain protein expressed in neurons, interacts with both the p55 TNF receptor (TNFR) type 1 and JNK3, placing it at a critical juncture in regulating signaling of neurodegeneration. We examined expression and interactions of the TNFR1 binding proteins, DENN/MADD, and TNFR-associated death domain (TRADD) protein in AD-affected tissues and cell cultures. We found reduced DENN/MADD and increased TRADD expression immunohistochemically in the hippocampus in areas of AD pathology compared to normal controls but little intraneuronal colocalization. In brain homogenates, DENN/MADD protein and mRNA expression was significantly reduced in AD compared to controls. Conversely, TRADD, TNFR1, and activated JNK were increased. Murine neuroblastoma and rat hippocampal cultures stressed with Abeta1-42 and the cortices of AD transgenic mice (Tg2576Swe) each showed decreased DENN/MADD expression and TRADD up-regulation in the mice, compared to controls. DENN/MADD antisense treatment of cultured rat hippocampal neurons reduced endogenous DENN/MADD and promoted neuronal cell death. DENN/MADD and TRADD competitively bound to TNFR1 when overexpressed in N(2)A cells, with DENN/MADD abrogating TNFR1 binding to TRADD. DENN/MADD may therefore be protective by inhibiting TRADD-induced apoptotic cell death. Reduction of DENN/MADD may affect long-term neuronal viability in AD by allowing TRADD mediation of TNFR1 signaling in response to oxidative or cytokine-promoted stresses.
 ...
PMID:Down-regulation of DENN/MADD, a TNF receptor binding protein, correlates with neuronal cell death in Alzheimer's disease brain and hippocampal neurons. 1500 67