The roles of ASK family proteins in stress responses and diseases

Hattori, Kazuki; Naguro, Isao; Runchel, Christopher; Ichijo, Hidenori

doi:10.1186/1478-811x-7-9

Cited by 176 publications

(156 citation statements)

References 61 publications

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“…40,41 As Dock3 protects RGCs from oxidative stress, the combination of Dock3 overexpression and inhibition of ASK1 signaling by a specific inhibitor 42 may be further available for the management of glaucoma. One important point is that glaucoma is a complex disease resulting from the confluence of various factors.…”

Section: -37mentioning

confidence: 99%

Dock3 attenuates neural cell death due to NMDA neurotoxicity and oxidative stress in a mouse model of normal tension glaucoma

et al. 2013

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Dedicator of cytokinesis 3 (Dock3), a new member of the guanine nucleotide exchange factors for the small GTPase Rac1, promotes axon regeneration following optic nerve injury. In the present study, we found that Dock3 directly binds to the intracellular C-terminus domain of NR2B, an N-methyl-D-aspartate (NMDA) receptor subunit. In transgenic mice overexpressing Dock3 (Dock3 Tg), NR2B expression in the retina was significantly decreased and NMDA-induced retinal degeneration was ameliorated. In addition, overexpression of Dock3 protected retinal ganglion cells (RGCs) from oxidative stress. We previously reported that glutamate/aspartate transporter (GLAST) is a major glutamate transporter in the retina, and RGC degeneration due to glutamate neurotoxicity and oxidative stress is observed in GLAST-deficient (KO) mice. In GLAST KO mice, the NR2B phosphorylation rate in the retina was significantly higher compared with Dock3 Tg:GLAST KO mice. Consistently, glaucomatous retinal degeneration was significantly improved in GLAST KO:Dock3 Tg mice compared with GLAST KO mice. These results suggest that Dock3 overexpression prevents glaucomatous retinal degeneration by suppressing both NR2B-mediated glutamate neurotoxicity and oxidative stress, and identifies Dock3 signaling as a potential therapeutic target for both neuroprotection and axonal regeneration.

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Section: -37mentioning

confidence: 99%

Dock3 attenuates neural cell death due to NMDA neurotoxicity and oxidative stress in a mouse model of normal tension glaucoma

et al. 2013

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“…2−4 ASK1-deficient mice display reduced levels of cardiomyocyte apoptosis, hypertrophy, and interstitial fibrosis. 5 Thus, selective inhibition of ASK1 represents an attractive strategy for slowing or potentially reversing harmful tissue changes associated with various forms of heart failure.…”

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confidence: 99%

Structure-Based Design of ASK1 Inhibitors as Potential Agents for Heart Failure

Lanier

Pickens

Bigi

et al. 2017

ACS Med. Chem. Lett.

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Apoptosis signal-regulating kinase 1 (ASK1/ MAP3K) is a mitogen-activated protein kinase family member shown to contribute to acute ischemia/reperfusion injury. Using structure-based drug design, deconstruction, and reoptimization of a known ASK1 inhibitor, a lead compound was identified. This compound displayed robust MAP3K pathway inhibition and reduction of infarct size in an isolated perfused heart model of cardiac injury. KEYWORDS:Apoptosis signal-regulating kinase 1 (ASK1), structure-based drug design (SBDD), cardiac injury A poptosis signal-regulating kinase 1 (ASK1) is a mitogenactivated protein kinase kinase kinase (MAP3K) family member residing upstream of both Jun N-terminal kinase (JNK) and p38. ASK1 is capable of activating JNK and P38 via the phosphorylation of intermediate kinases. ASK1 plays a role in the mammalian cell stress response and the induction of apoptotic cell death. It also contributes to a range of systemic diseases including heart failure 1 and acute ischemia/reperfusion injury, by reducing structural and functional integrity of the mitochondria in cardiac cells. 2−4 ASK1-deficient mice display reduced levels of cardiomyocyte apoptosis, hypertrophy, and interstitial fibrosis. 5 Thus, selective inhibition of ASK1 represents an attractive strategy for slowing or potentially reversing harmful tissue changes associated with various forms of heart failure.Using ASK1 structural information and deconstruction of known ASK1 inhibitors such as 1 and 2 (Figure 1), our research team generated a novel, potent, and orally bioavailable ASK1 inhibitor with favorable physicochemical properties to help further elucidate the role of ASK1 in cardiac injury. Compound 1 was an early lead for Takeda's ASK1 inhibitor program. 6 Compound 2 (GS-4997, Gilead Sciences) is a clinical stage ASK1 inhibitor, which has been evaluated as an experimental treatment for diabetic nephropathy and kidney fibrosis. 7 Key structural features with respect to ligand interactions within the ATP binding site were identified using our internal database as well as public domain crystal structures of small molecules in ASK1 and published pharmacophore models. 8,9 Figure 1 illustrates the cocrystal structure of 1 in hASK1 (PDB: 3VW6) and highlights the key interactions between 1 and the ASK1 ATP binding pocket. Binding to the kinase hinge is characterized by a hydrogen bonding interaction with the

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“…Flavonoids have many pharmacological and biological activities including anti-oxidative (Powis & Kirkpatrick 2007;Hattori et al 2009), anti-inflammatory, and antitumor ones. The molecular mechanisms responsible for these protective effects of flavonoids may include not only their anticancer activities but also their interaction with signaling cascades leading to cell death.…”

Section: Discussionmentioning

confidence: 99%

Induction of apoptosis in HT-29 cells by quercetin through mitochondria-mediated apoptotic pathway

Gao

2013

Animal Cells and Systems

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With increasing use of natural plant-derived components, exploring the anti-proliferative effects of phytochemicals is increasingly gaining importance in designing anticancer drugs. Quercetin, a natural constituent abundantly present in food products, is capable of inducing apoptosis in tumor cells. However, little is known about its biological effect on colon cancer cells and molecular mechanism leading to this event. The aim of this study was to investigate the effect of quercetin on the apoptotic pathway in human colon carcinoma cells (HT-29 cells). The results indicated that quercetin induced suppression of cell viability and apoptosis in HT-29 cells in a dose-dependent manner. This involved characteristic changes in nuclear morphology, activation of caspases-3 and caspases-9, collapse of Mitochondrial membrane potential (DCm), upregulation of pro-apoptotic Bax, and downregulation of antiapoptotic Bcl-2 and Bcl-XL. Quercetin, which exerts anti-proliferative effect though different signaling pathways, is a classic candidate for anti-colon cancer drug design.

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The roles of ASK family proteins in stress responses and diseases

Cited by 176 publications

References 61 publications

Dock3 attenuates neural cell death due to NMDA neurotoxicity and oxidative stress in a mouse model of normal tension glaucoma

Dock3 attenuates neural cell death due to NMDA neurotoxicity and oxidative stress in a mouse model of normal tension glaucoma

Structure-Based Design of ASK1 Inhibitors as Potential Agents for Heart Failure

Induction of apoptosis in HT-29 cells by quercetin through mitochondria-mediated apoptotic pathway

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