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)

Macrophages comprise the major population of cells infiltrating pancreatic islets during the early stages of infection in DBA/2 mice by the D variant of encephalomyocarditis virus (EMC-D virus). Inactivation of macrophages prior to viral infection almost completely prevents EMC-D virus-induced diabetes. This investigation was initiated to determine whether a tyrosine kinase signalling pathway might be involved in the activation of macrophages by EMC-D virus infection and whether tyrosine kinase inhibitors might, therefore, abrogate EMC-D virus-induced diabetes in vivo. When isolated macrophages were infected with EMC-D virus, inducible nitric oxide synthase mRNA was expressed and nitric oxide was subsequently produced. Treatment of macrophages with the tyrosine kinase inhibitor tyrphostin AG126, but not tyrphostin AG556, prior to EMC-D virus infection blocked the production of nitric oxide. The infection of macrophages with EMC-D virus also resulted in the activation of the mitogen-activated protein kinases (MAPKs) p42(MAPK/ERK2)/p44(MAPK/ERK1), p38(MAPK), and p46/p54(JNK). In accord with the greater potency of AG126 than of AG556 in blocking EMC-D virus-mediated macrophage activation, the incidence of diabetes in EMC-D virus-infected mice treated with AG126 (25%) was much lower than that in AG556-treated (75%) or vehicle-treated (88%) control mice. We conclude that EMC-D virus-induced activation of macrophages resulting in macrophage-mediated beta-cell destruction can be prevented by the inhibition of a tyrosine kinase signalling pathway involved in macrophage activation.
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PMID:Prevention of encephalomyocarditis virus-induced diabetes in mice by inhibition of the tyrosine kinase signalling pathway and subsequent suppression of nitric oxide production in macrophages. 1048 7

The expression of mitogen-activated protein kinases (MAPK) in DBA/2-pcy/pcy (pcy) mice, a murine model of polycystic kidney disease was investigated. Proliferating cell nuclear antigen-positive cells were recognized in cyst epithelium from embryonic day 14.5 to 25 wk of age. Extracellular signal-regulated kinase (ERK) was expressed in the renal tubules of control and pcy mice, but stronger immunostaining was observed in cyst epithelium. Phosphorylated ERK was detected only in pcy mice and was localized predominantly in the cysts. p38 MAPK (p38) was no longer expressed after birth in controls but was detected in the cyst epithelium and in occasional tubular cells of pcy mice at all stages examined. c-Jun N-terminal kinase (JNK) was expressed in all tubular segments of controls after neonatal day 7, whereas in pcy kidneys, tubules became positive for JNK after 8 wk, and the cysts expressed little JNK. Administration of an oral MAP/ERK kinase inhibitor, PD184352, 400 mg/kg per d, to 10-wk-old pcy mice daily for the first week and then every third day for 6 additional weeks significantly decreased BP, kidney weight, serum creatinine level, and water intake and significantly increased urine osmolality. The cystic index and expression of phosphorylated ERK and ERK were significantly lower in PD184352-treated pcy mice. These results demonstrate that the expression of MAPK is dysregulated in cyst epithelium and that inhibition of ERK slowed the progression of renal disease in pcy mice.
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PMID:Extracellular signal-regulated kinase inhibition slows disease progression in mice with polycystic kidney disease. 1668 24

Glaucoma is the second leading cause of blindness in the world. The ultimate cause of vision loss due to glaucoma is thought to be retinal ganglion cell (RGC) apoptosis. Neuroprotection of RGC is becoming an important approach of glaucoma therapy. Several lines of evidence suggest that estrogen has neurotrophic and neuroprotective properties. In this study, we examine the role of estrogen in preventing RGC loss in DBA/2J mouse, an in vivo model of an inherited (pigmentary) glaucoma. Two-month-old female DBA/2J mice were anesthetized and ovariectomized with or without subcutaneous 17beta-estradiol (betaE2) pellet implantation. RGC survival was evaluated from flat-mounted whole retinas by counting retrograde-labeled cells. The loss of nerve fibers and RGC were also evaluated in paraffin-fixed retinal cross sections. Biochemical alterations in the retinas of DBA/2J mice in response to systemic injection of betaE2 were also examined. We have made several important observations showing that: (1) betaE2 treatment reduced the loss of RGC and neurofibers through inhibition of ganglion cell apoptosis, (2) betaE2 activated Akt and cAMP-responsive-element-binding-protein (CREB), (3) betaE2 up-regulated thioredoxin-1 (Trx-1) expression, (4) betaE2 reduced the increased activations of mitogen-activated protein kinases (MAPK) and NF-kappaB, (5) betaE2 inhibited the increased interleukin-18 (IL-18) expression, and (6) treatment with tamoxifen, an estrogen receptor antagonist, blocked betaE2-mediated activation of Akt and inhibition of MAPK phosphorylation in the retinas of DBA/2J mice. These findings suggest the possible involvement of multiple biochemical events, including estrogen receptor/Akt/CREB/thioredoxin-1, and estrogen receptor/MAPK/NF-kappaB, in estrogen-mediated retinal ganglion cell protection.
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PMID:Retinal ganglion cell protection by 17-beta-estradiol in a mouse model of inherited glaucoma. 1744 11