Disease relevance of Map3k5

• Consistent with this, ASK1-deficient mice were resistant to lipopolysaccharide-induced septic shock [1].
• The ablation of ASK1 rescued heart dysfunction and dilatation as well as cardiac fibrosis [2].
• Execution of macrophage apoptosis by Mycobacterium avium through apoptosis signal-regulating kinase 1/p38 mitogen-activated protein kinase signaling and caspase 8 activation [3].
• Thus, inhibition of the ASK1-p38 pathway could be useful for the treatment of neurodegenerative diseases including glaucoma [4].
• Enhanced TNF-alpha-induced apoptosis in Fanconi anemia type C-deficient cells is dependent on apoptosis signal-regulating kinase 1 [5].

Psychiatry related information on Map3k5

• These results indicate that ROS-mediated ASK1 activation is a key mechanism for Abeta-induced neurotoxicity, which plays a central role in Alzheimer's disease [6].

High impact information on Map3k5

• Apoptosis signal-regulating kinase 1 (ASK1) is an evolutionarily conserved mitogen-activated protein 3-kinase that activates both Jnk and p38 mitogen-activated protein kinases [1].
• ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity [1].
• Our data demonstrate that the reactive oxygen species-dependent TRAF6-ASK1-p38 axis is crucial for TLR4-mediated mammalian innate immunity [1].
• Overexpression of a constitutively active mutant of ASK1 induced apoptosis in isolated rat neonatal cardiomyocytes, whereas neonatal ASK-/- cardiomyocytes were resistant to H2O2-induced apoptosis [7].
• Thus, ASK1 plays an important role in regulating left ventricular remodeling by promoting apoptosis [7].

Chemical compound and disease context of Map3k5

• These results provided the first in vivo evidence that ASK1 is the critical signaling molecule for Ang II-induced cardiac hypertrophy and remodeling [8].
• Apoptosis signal-regulating kinase 1 plays a pivotal role in angiotensin II-induced cardiac hypertrophy and remodeling [8].
• These findings indicate that edaravone significantly attenuates pressure overload-induced cardiac hypertrophy mediated through its antioxidative function and subsequent inhibition of ASK1 signaling pathway [9].

Biological context of Map3k5

• 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 [4].
• Interestingly, ischemia-induced phosphorylation of p38 mitogen-activated protein kinase (p38), which mediates RGC apoptosis, was almost completely suppressed in ASK1 KO mice [4].
• Our findings suggest that ASK1 is involved in the neural cell apoptosis after various kinds of oxidative stress [4].
• Targeted deletion of apoptosis signal-regulating kinase 1 attenuates left ventricular remodeling [7].
• Here, we examined whether altered Ask1 signaling participated in the proapoptotic phenotype of primary Fancc-/- MEFs and hematopoietic progenitors treated with the myelosuppressive cytokine tumor necrosis factor-alpha (TNF-alpha) [5].

Anatomical context of Map3k5

• Apoptosis signal-regulating kinase 1 (ASK1) was activated in Mycobacterium avium-treated macrophages and in turn activated p38 mitogen-activated protein (MAP) kinase [3].
• To support this mechanism we demonstrate that the production of ROS by ROT treated AML12 hepatocyte cells dissociates the Trx-ASK1 complex, thereby increasing p38 MAPK pathway activity [10].
• Recent data in Fancc-/- murine embryonic fibroblasts (MEFs) implicate increased oxidant-induced apoptotic signaling through the redox-dependent protein, apoptosis signal-regulating kinase 1 (Ask1) [5].
• A T cell hybrid transfected with a kinase-dead apoptosis-signal-regulating kinase 1 fails to activate p38 MAPK in response to 4-1BB signaling [11].
• Ca2+ influx evoked by membrane depolarization in primary neurons and synaptosomes induced activation of p38, which was impaired in those derived from ASK1-deficient mice [12].

Associations of Map3k5 with chemical compounds

• Liver protection from apoptosis requires both blockage of initiator caspase activities and inhibition of ASK1/JNK pathway via glutathione S-transferase regulation [13].
• ASK1(-/-) cardiomyocytes were more resistant to H(2)O(2)- or Ca(2+)-induced apoptotic and non-apoptotic cell death compared with wild-type cells [14].
• Left ventricular (LV) ASK1 was activated by Ang II infusion in wild-type mice, which was mediated by angiotensin II type 1 receptor and superoxide [8].
• Treatment of a specific p38 inhibitor (SB203580) or overexpression of a kinase-defective mutant, ASK1 (K709R), promoted Fas-mediated cell death in HepG2 cells [15].
• Bromodeoxyuridine labeling index at 7 days after injury showed that DN-ASK1 remarkably suppressed VSMC proliferation in both the intima and the media [16].
• Transfection with an adenoviral construct including a dominant negative form of ASK1 gene significantly inhibited SA-beta-gal activity induced by high glucose [17].

Regulatory relationships of Map3k5

• Thus, ASK1 is selectively required for TNF- and oxidative stress-induced sustained activations of JNK/p38 and apoptosis [18].
• Ca2+/calmodulin-dependent protein kinase type II (CaMKII) activated ASK1 by phosphorylation [12].

Other interactions of Map3k5

• Thioredoxin-ASK1 complex levels regulate ROS-mediated p38 MAPK pathway activity in livers of aged and long-lived Snell dwarf mice [10].
• We demonstrated that this kinase pathway was strongly inhibited in the presence of Me(2)SO whereas overexpression of ASK1 was able to restore caspase-3 activity and apoptosis [13].
• Apoptosis signal-regulating kinase 1 (ASK1), one of mitogen-activated protein kinase kinase kinases, plays a key role in stress-induced cellular responses [8].
• Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays an important role in stress-induced apoptosis [7].
• Moreover, p38 activation induced by the expression of constitutively active CaMKII required endogenous ASK1 [12].
• MPK38-mediated ASK1 activation was induced through the increased interaction between ASK1 and its substrate MKK3 [19].

Analytical, diagnostic and therapeutic context of Map3k5

• Molecular cloning and characterization of the mouse apoptosis signal-regulating kinase 1 [20].
• Northern blot analysis identified a 6-kb transcript of ASK1 which is expressed in the various mouse adult tissues including heart, brain, lung, liver and kidney [20].

References