Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.25 (MEKK1)
 1,856 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays an important role in oxidative stress-induced apoptosis. In the present study, we used ASK1 knockout (KO) mice to examine the possibility that ASK1 is involved in the neural cell apoptosis that occurs during retinal development and ischemic injury. ASK1 was expressed in retinal neurons, including retinal ganglion cells (RGCs), but retinal structure and extent of cell death during development were normal in ASK1 KO mice. On the other hand, the strain was less susceptible to ischemic injury, and the number of surviving retinal neurons was significantly increased compared with that in wild-type mice. Interestingly, ischemia-induced phosphorylation of p38 mitogen-activated protein kinase (p38), which mediates RGC apoptosis, was almost completely suppressed in ASK1 KO mice. In such retinas, the numbers of cleaved caspase-3- and TUNEL-positive neurons were apparently decreased compared with those in wild-type mice. Furthermore, cultured RGCs from ASK1 KO mice were resistant to H(2)O(2)-induced apoptosis. Our findings suggest that ASK1 is involved in the neural cell apoptosis after various kinds of oxidative stress. Thus, inhibition of the ASK1-p38 pathway could be useful for the treatment of neurodegenerative diseases including glaucoma.
 ...
PMID:Role of apoptosis signal-regulating kinase 1 in stress-induced neural cell apoptosis in vivo. 1640 28

Spermidine acts as an endogenous free radical scavenger and inhibits the action of reactive oxygen species. In this study, we examined the effects of spermidine on retinal ganglion cell (RGC) death in a mouse model of optic nerve injury (ONI). Daily ingestion of spermidine reduced RGC death following ONI and sequential in vivo retinal imaging revealed that spermidine effectively prevented retinal degeneration. Apoptosis signal-regulating kinase-1 (ASK1) is an evolutionarily conserved mitogen-activated protein kinase kinase kinase and has an important role in ONI-induced RGC apoptosis. We demonstrated that spermidine suppresses ONI-induced activation of the ASK1-p38 mitogen-activated protein kinase pathway. Moreover, production of chemokines important for microglia recruitment was decreased with spermidine treatment and, consequently, accumulation of retinal microglia is reduced. In addition, the ONI-induced expression of inducible nitric oxide synthase in the retina was inhibited with spermidine treatment, particularly in microglia. Furthermore, daily spermidine intake enhanced optic nerve regeneration in vivo. Our findings indicate that spermidine stimulates neuroprotection as well as neuroregeneration, and may be useful for treatment of various neurodegenerative diseases including glaucoma.
...
PMID:Spermidine promotes retinal ganglion cell survival and optic nerve regeneration in adult mice following optic nerve injury. 2588 87

Glaucoma is a neurodegenerative disease of the eye and it is one of the major causes of blindness. Glaucoma is usually associated with elevated intraocular pressure (IOP) and the current therapy focuses on reduction of IOP. However, neuroprotective strategies could also be beneficial for treatment of glaucoma because the pathology of the disease involves retinal ganglion cell (RGC) death and damage to the optic nerve. Dedicator of cytokinesis 3 (Dock3) is an atypical guanine exchange factor (GEF) that belongs to a family of Dock proteins, Dock1-11. Dock3 exerts neuroprotective effects on the retina and optic nerve, and studies revealed that some of the Dock3-mediated effects are GEF-independent. One of these mechanisms is that Dock3 directly binds to the GluN2B subunit of the N-methyl-D-aspartate (NMDA) receptor. Upon stimulation by NMDA or optic nerve crush, overexpression of Dock3 promotes internalization and degradation of the NMDA receptor in the retina in vivo. It is suggested that this process is mediated by inhibition of Fyn, a Src family tyrosine kinase. Reduction in NMDA receptor expression results in decreased excitotoxic damage and oxidative stress, thereby promoting RGC survival. In this review, we discuss the therapeutic potential of neuroprotection for glaucoma and the effects of Dock3 on NMDA receptors. We also discuss apoptosis signal-regulating kinase 1 (ASK1), a member of mitogen-activated protein kinase kinase kinase that is a key regulator of cellular responses to oxidative stress, as an innovative therapeutic target for glaucoma.
 ...
PMID:Dock3-NMDA receptor interaction as a target for glaucoma therapy. 2761 13