Genomes and Genes
map kinase kinase kinase 5
Summary: A 150-kDa MAP kinase kinase kinase that may play a role in the induction of APOPTOSIS. It has specificity for MAP KINASE KINASE 3; MAP KINASE KINASE 4; and MAP KINASE KINASE 6.
- Noh K, Cho S, Choi E. Knockdown of apoptosis signal-regulating kinase 1 modulates basal glycogen synthase kinase-3? kinase activity and regulates cell migration. FEBS Lett. 2010;584:4097-101 pubmed publisher..Together, the blockage of the GSK-3?-?-catenin pathway resulting from the knockdown of ASK1 modulates the migration of breast cancer cells. ..
- Imoto K, Kukidome D, Nishikawa T, Matsuhisa T, Sonoda K, Fujisawa K, et al. Impact of mitochondrial reactive oxygen species and apoptosis signal-regulating kinase 1 on insulin signaling. Diabetes. 2006;55:1197-204 pubmed..These results suggest that TNF-alpha increases mitochondrial ROS and activates ASK1 in Huh7 cells and that these TNF-alpha-induced phenomena contribute, at least in part, to impaired insulin signaling. ..
- Liu G, Guo H, Guo C, Zhao S, Gong D, Zhao Y. Involvement of IRE1? signaling in the hippocampus in patients with mesial temporal lobe epilepsy. Brain Res Bull. 2011;84:94-102 pubmed publisher..Our data suggest that chronic epilepsy is associated with ER stress, as well as induction of both IRE1?-mediated pro- and anti-apoptotic signaling pathways. ..
- Harada C, Nakamura K, Namekata K, Okumura A, Mitamura Y, Iizuka Y, et al. Role of apoptosis signal-regulating kinase 1 in stress-induced neural cell apoptosis in vivo. Am J Pathol. 2006;168:261-9 pubmed..Thus, inhibition of the ASK1-p38 pathway could be useful for the treatment of neurodegenerative diseases including glaucoma. ..
- Guo X, Harada C, Namekata K, Matsuzawa A, Camps M, Ji H, et al. Regulation of the severity of neuroinflammation and demyelination by TLR-ASK1-p38 pathway. EMBO Mol Med. 2010;2:504-15 pubmed publisher..These results suggest that the TLR-ASK1-p38 pathway in glial cells may serve as a valid therapeutic target for autoimmune demyelinating disorders including multiple sclerosis. ..
- Kumakura K, Nomura H, Toyoda T, Hashikawa K, Noguchi T, Takeda K, et al. Hyperactivity in novel environment with increased dopamine and impaired novelty preference in apoptosis signal-regulating kinase 1 (ASK1)-deficient mice. Neurosci Res. 2010;66:313-20 pubmed publisher..Our findings thus demonstrate novel behavioral functions of ASK1, including regulation of locomotor activity, novelty preference, and motor coordination with dopaminergic transmission. ..
- Liu Q, Sargent M, York A, Molkentin J. ASK1 regulates cardiomyocyte death but not hypertrophy in transgenic mice. Circ Res. 2009;105:1110-7 pubmed publisher..These results indicate that ASK1 does not directly regulate the cardiac hypertrophic response in vivo, but it does alter cell death and propensity to cardiomyopathy, in part, through a calcineurin-dependent mechanism. ..
- Okamoto M, Saito N, Kojima H, Okabe T, Takeda K, Ichijo H, et al. Identification of novel ASK1 inhibitors using virtual screening. Bioorg Med Chem. 2011;19:486-9 pubmed publisher..We identified novel ASK1 inhibitors by virtual screening from the public chemical library collected by Chemical Biology Research Initiative (CBRI) at the University of Tokyo. ..
- Hayakawa Y, Hirata Y, Nakagawa H, Sakamoto K, Hikiba Y, Kinoshita H, et al. Apoptosis signal-regulating kinase 1 and cyclin D1 compose a positive feedback loop contributing to tumor growth in gastric cancer. Proc Natl Acad Sci U S A. 2011;108:780-5 pubmed publisher..These results indicate an autoregulatory mechanism of ASK1 in the development of gastric cancer. Targeting this positive feedback loop, ASK1 may present a potential therapeutic target for the treatment of advanced gastric cancer. ..
- Norman P. Evaluation of WO2012003387, Gilead's ASK1 inhibitors. Expert Opin Ther Pat. 2012;22:455-9 pubmed publisher..The claimed compounds define a pharmacophore, distinct from that described in the limited number of patent filings claiming ASK1 inhibitors. ..
- Waak J, Weber S, Görner K, Schall C, Ichijo H, Stehle T, et al. Oxidizable residues mediating protein stability and cytoprotective interaction of DJ-1 with apoptosis signal-regulating kinase 1. J Biol Chem. 2009;284:14245-57 pubmed publisher..We suggest that impairments in oxidative conformation changes of DJ-1 might contribute to PD neurodegeneration. ..
- Takenouchi T, Setoguchi T, Yone K, Komiya S. Expression of apoptosis signal-regulating kinase 1 in mouse spinal cord under chronic mechanical compression: possible involvement of the stress-activated mitogen-activated protein kinase pathways in spinal cord cell apoptosis. Spine (Phila Pa 1976). 2008;33:1943-50 pubmed publisher..To examine apoptosis signal cascade in neurons and oligodendrocytes under the chronic spinal cord compression of tiptoe-walking Yoshimura (TWY) mouse, which is model of progressive cervical cord compression...
- Hori M, Nishida K. Oxidative stress and left ventricular remodelling after myocardial infarction. Cardiovasc Res. 2009;81:457-64 pubmed publisher..Since the extent of LV remodelling is a major predictor of prognosis of the patients with MI, the therapeutic approach to attenuating LV remodelling is critically important. ..
- Yamamoto E, Dong Y, Kataoka K, Yamashita T, Tokutomi Y, Matsuba S, et al. Olmesartan prevents cardiovascular injury and hepatic steatosis in obesity and diabetes, accompanied by apoptosis signal regulating kinase-1 inhibition. Hypertension. 2008;52:573-80 pubmed publisher..Moreover, the beneficial effects of angiotensin II inhibition on dietary diabetic mice seem to be mediated by the inhibition of ASK1 activation. ..
- Matsuzawa A, Ichijo H. Redox control of cell fate by MAP kinase: physiological roles of ASK1-MAP kinase pathway in stress signaling. Biochim Biophys Acta. 2008;1780:1325-36 pubmed publisher..In this review, we focus on redox control of cell function by MAP kinase signaling, and provide the advanced mechanism of redox-regulated ASK1 activation and physiological roles of the ASK1-MAP kinase pathway in stress signaling. ..
- Nishida K, Otsu K. The role of apoptosis signal-regulating kinase 1 in cardiomyocyte apoptosis. Antioxid Redox Signal. 2006;8:1729-36 pubmed..In cardiomyocytes, ASK1 is involved not only in cardiac apoptosis, leading to cardiac remodeling, but also in cardiac hypertrophy as well as nonapoptotic cardiomyocyte death. ..
- Hsieh C, Papaconstantinou J. Thioredoxin-ASK1 complex levels regulate ROS-mediated p38 MAPK pathway activity in livers of aged and long-lived Snell dwarf mice. FASEB J. 2006;20:259-68 pubmed
- Yang C, Shin D, Lee H, Son J, Lee S, Akira S, et al. ASK1-p38 MAPK-p47phox activation is essential for inflammatory responses during tuberculosis via TLR2-ROS signalling. Cell Microbiol. 2008;10:741-54 pubmed..The altered regulation of this axis with an increasing free-radical burden may contribute to the immunopathogenesis of human TB. ..
- Mnich S, Blanner P, Hu L, Shaffer A, Happa F, O NEIL S, et al. Critical role for apoptosis signal-regulating kinase 1 in the development of inflammatory K/BxN serum-induced arthritis. Int Immunopharmacol. 2010;10:1170-6 pubmed publisher..This study is the first to suggest that ASK1 is critical for the development of RA and that ASK1 may be involved in the production of proinflammatory mediators in response to TNF-? stimulation in the RA joint. ..
- Im J, Lee K, Junn E, Mouradian M. DJ-1 protects against oxidative damage by regulating the thioredoxin/ASK1 complex. Neurosci Res. 2010;67:203-8 pubmed publisher..These findings point to yet another mechanism through which DJ-1 has anti-oxidant and cytoprotective properties by regulating the Trx1/ASK1 complex and controlling the availability of ASK1 to effect apoptosis. ..
- Junn E, Taniguchi H, Jeong B, Zhao X, Ichijo H, Mouradian M. Interaction of DJ-1 with Daxx inhibits apoptosis signal-regulating kinase 1 activity and cell death. Proc Natl Acad Sci U S A. 2005;102:9691-6 pubmed..These findings suggest that the regulated sequestration of Daxx in the nucleus and keeping apoptosis signal-regulating kinase 1 activation in check is a critical mechanism by which DJ-1 exerts its cytoprotective function. ..
- Honmo S, Ozaki A, Yamamoto M, Hashimoto N, Miyakoshi M, Tanaka H, et al. Low p38 MAPK and JNK activation in cultured hepatocytes of DRH rats; a strain highly resistant to hepatocarcinogenesis. Mol Carcinog. 2007;46:758-65 pubmed..The low activation of the stress-activated protein kinases may be linked to the resistance to cellular stress, which may underlie the hepatocarcinogenesis-resistance in DRH rats. ..
- Taniike M, Yamaguchi O, Tsujimoto I, Hikoso S, Takeda T, Nakai A, et al. Apoptosis signal-regulating kinase 1/p38 signaling pathway negatively regulates physiological hypertrophy. Circulation. 2008;117:545-52 pubmed publisher..These results indicate that the ASK1/p38 signaling pathway negatively regulates physiological hypertrophy. ..
- Holasek S, Wengenack T, Kandimalla K, Montano C, Gregor D, Curran G, et al. Activation of the stress-activated MAP kinase, p38, but not JNK in cortical motor neurons during early presymptomatic stages of amyotrophic lateral sclerosis in transgenic mice. Brain Res. 2005;1045:185-98 pubmed..Consequently, these enzymes may provide the biochemical markers to enable earlier diagnosis of ALS and molecular targets for the development of new therapeutic compounds. ..
- Zhang C, Zhang M, Shen Y, Burks J, Zhang Y, Wang J, et al. TNF-alpha suppresses prolyl-4-hydroxylase alpha1 expression via the ASK1-JNK-NonO pathway. Arterioscler Thromb Vasc Biol. 2007;27:1760-7 pubmed..Further understanding of this pathway may facilitate development of novel therapeutics for vascular diseases. ..
- Liu H, Zhang H, Iles K, Rinna A, Merrill G, Yodoi J, et al. The ADP-stimulated NADPH oxidase activates the ASK-1/MKK4/JNK pathway in alveolar macrophages. Free Radic Res. 2006;40:865-74 pubmed
- Mochizuki T, Furuta S, Mitsushita J, Shang W, Ito M, Yokoo Y, et al. Inhibition of NADPH oxidase 4 activates apoptosis via the AKT/apoptosis signal-regulating kinase 1 pathway in pancreatic cancer PANC-1 cells. Oncogene. 2006;25:3699-707 pubmed..Taken together, these findings suggest that ROS generated by Nox4, at least in part, transmit cell survival signals through the AKT-ASK1 pathway in pancreatic cancer cells and their depletion leads to apoptosis. ..
- Stark M, Woods S, Gartside M, Bonazzi V, Dutton Regester K, Aoude L, et al. Frequent somatic mutations in MAP3K5 and MAP3K9 in metastatic melanoma identified by exome sequencing. Nat Genet. 2011;44:165-9 pubmed publisher..Attenuation of MAP3K9 function in melanoma cells using siRNA led to increased cell viability after temozolomide treatment, suggesting that decreased MAP3K pathway activity can lead to chemoresistance in melanoma. ..
- Nadeau P, Charette S, Landry J. REDOX reaction at ASK1-Cys250 is essential for activation of JNK and induction of apoptosis. Mol Biol Cell. 2009;20:3628-37 pubmed publisher..They also clarify the thiol reductase function of Trx1 on ASK1 activity. ..
- Galvan V, Banwait S, Spilman P, Gorostiza O, Peel A, Ataie M, et al. Interaction of ASK1 and the beta-amyloid precursor protein in a stress-signaling complex. Neurobiol Dis. 2007;28:65-75 pubmed..Thus, ASK1 may be the apical MAPKKK in a signaling complex assembled with APP as a response to stress. ..
- Calvisi D, Pinna F, Pellegrino R, Sanna V, Sini M, Daino L, et al. Ras-driven proliferation and apoptosis signaling during rat liver carcinogenesis is under genetic control. Int J Cancer. 2008;123:2057-64 pubmed publisher..Dusp1 possesses a prominent role in the acquisition of the phenotype resistant to HCC by BN rats, whereas late activation of RassF1A/Nore1A and Dab2IP/Ask1 axes is implicated in the highest apoptosis characteristic of BN HCC...
- Hu X, Weng Z, Chu C, Zhang L, Cao G, Gao Y, et al. Peroxiredoxin-2 protects against 6-hydroxydopamine-induced dopaminergic neurodegeneration via attenuation of the apoptosis signal-regulating kinase (ASK1) signaling cascade. J Neurosci. 2011;31:247-61 pubmed publisher..Our results also suggest that PRX2 and ASK1 may be potential targets for neuroprotective intervention in PD. ..
- Seong H, Jung H, Ichijo H, Ha H. Reciprocal negative regulation of PDK1 and ASK1 signaling by direct interaction and phosphorylation. J Biol Chem. 2010;285:2397-414 pubmed publisher..These results provide evidence that PDK1 and ASK1 directly interact and phosphorylate each other and act as negative regulators of their respective kinases in resting cells. ..
- Terada Y, Inoshita S, Kuwana H, Kobayashi T, Okado T, Ichijo H, et al. Important role of apoptosis signal-regulating kinase 1 in ischemic acute kidney injury. Biochem Biophys Res Commun. 2007;364:1043-9 pubmed..These results demonstrated that ASK1 is activated in I/R-induced AKI, and blockage of ASK1 attenuates renal tubular apoptosis, MCP-1 expression, and renal function. ..
- Minn Y, Cho K, Kim H, Kim H, Suk S, Lee B, et al. Induction of apoptosis signal-regulating kinase 1 and oxidative stress mediate age-dependent vulnerability to 3-nitropropionic acid in the mouse striatum. Neurosci Lett. 2008;430:142-6 pubmed..Present results suggest that age-related upregulation of Ask1 and oxidative stress may mediate age-dependent striatal vulnerability to 3-NP. ..
- Kumasawa F, Hashimoto S, Onose A, Jibiki I, Mizumura K, Matsumoto K, et al. Apoptosis signal-regulating kinase 1 in leukotriene D(4)-induced activator protein-1 activation in airway smooth muscle cells. Eur J Pharmacol. 2005;517:11-6 pubmed..These results indicate that LTD(4) is capable of inducing AP-1 activation and ASK1 regulates AP-1 activation in LTD(4)-stimulated airway smooth muscle cells. ..
- Ren G, Huynh C, Bijian K, Cybulsky A. Role of apoptosis signal-regulating kinase 1 in complement-mediated glomerular epithelial cell injury. Mol Immunol. 2008;45:2236-46 pubmed publisher..e. when ASK1 is overexpressed, p38 activation is amplified, and C5b-9 assembly leads to GEC injury via ASK1 and p38. The present study thus defines a novel role for ASK1 as a mediator of C5b-9-dependent cell injury. ..
- Harada C, Namekata K, Guo X, Yoshida H, Mitamura Y, Matsumoto Y, et al. ASK1 deficiency attenuates neural cell death in GLAST-deficient mice, a model of normal tension glaucoma. Cell Death Differ. 2010;17:1751-9 pubmed publisher..These results suggest that ASK1 activation is involved in NTG-like pathology in both neural and glial cells and that interrupting ASK1-dependent pathways could be beneficial in the treatment of glaucoma, including NTG. ..
- Lim P, Liu J, Go M, Boelsterli U. The mitochondrial superoxide/thioredoxin-2/Ask1 signaling pathway is critically involved in troglitazone-induced cell injury to human hepatocytes. Toxicol Sci. 2008;101:341-9 pubmed..Furthermore, the data support our concept that targeted delivery of an antioxidant to mitochondria can inhibit upstream signaling and protect from troglitazone-induced lethal cell injury. ..
- Saito J, Toriumi S, Awano K, Ichijo H, Sasaki K, Kobayashi T, et al. Regulation of apoptosis signal-regulating kinase 1 by protein phosphatase 2Cepsilon. Biochem J. 2007;405:591-6 pubmed..These results suggest that PP2Cepsilon maintains ASK1 in an inactive state by dephosphorylation in quiescent cells, supporting the possibility that PP2Cepsilon and PP5 play different roles in H2O2-induced regulation of ASK1 activity. ..
- Kim S, Shim J, Chun E, Lee K. Reciprocal inhibition between the transforming growth factor-?-activated kinase 1 (TAK1) and apoptosis signal-regulating kinase 1 (ASK1) mitogen-activated protein kinase kinase kinases and its suppression by TAK1-binding protein 2 (TAB2), an adapter . J Biol Chem. 2012;287:3381-91 pubmed publisher..Overall, these results demonstrate that TAK1 and its adapter protein, TAB2, reciprocally regulate both TAK1- and ASK1-mediated signaling pathways to direct the activations of NF-?B and AP-1. ..
- Yan W, Arai A, Aoki M, Ichijo H, Miura O. ASK1 is activated by arsenic trioxide in leukemic cells through accumulation of reactive oxygen species and may play a negative role in induction of apoptosis. Biochem Biophys Res Commun. 2007;355:1038-44 pubmed..These results indicate that ASK1 is activated by ATO through ROS accumulation and may negatively regulate apoptosis in leukemic cells without activating p38 and JNK. ..
- Nagai H, Noguchi T, Homma K, Katagiri K, Takeda K, Matsuzawa A, et al. Ubiquitin-like sequence in ASK1 plays critical roles in the recognition and stabilization by USP9X and oxidative stress-induced cell death. Mol Cell. 2009;36:805-18 pubmed publisher..These results demonstrate that USP9X-dependent stabilization of activated ASK1 plays a crucial role in oxidative stress-induced cell death. ..
- Hayakawa Y, Hirata Y, Nakagawa H, Sakamoto K, Hikiba Y, Otsuka M, et al. Apoptosis signal-regulating kinase 1 regulates colitis and colitis-associated tumorigenesis by the innate immune responses. Gastroenterology. 2010;138:1055-67.e1-4 pubmed publisher..In the CAC model, ASK1(-/-) mice developed more numerous and larger tumors than WT mice through increased colonic inflammation. ASK1 controls the development of intestinal inflammation and CAC through the regulation of innate immunity. ..
- Kundu M, Pathak S, Kumawat K, Basu S, Chatterjee G, Pathak S, et al. A TNF- and c-Cbl-dependent FLIP(S)-degradation pathway and its function in Mycobacterium tuberculosis-induced macrophage apoptosis. Nat Immunol. 2009;10:918-26 pubmed publisher..Our findings identify a previously unappreciated signaling pathway needed for Mycobacterium tuberculosis-triggered macrophage cell death. ..
- Zhang H, Tao L, Jiao X, Gao E, Lopez B, Christopher T, et al. Nitrative thioredoxin inactivation as a cause of enhanced myocardial ischemia/reperfusion injury in the aging heart. Free Radic Biol Med. 2007;43:39-47 pubmed..Interventions that restore Trx activity in the aging heart may be novel therapies to attenuate MI/R injury in aging patients. ..
- Zhou J, Shao Z, Kerkela R, Ichijo H, Muslin A, Pombo C, et al. Serine 58 of 14-3-3zeta is a molecular switch regulating ASK1 and oxidant stress-induced cell death. Mol Cell Biol. 2009;29:4167-76 pubmed publisher..Our findings identify a novel pathway that regulates ASK1 activation and oxidant stress-induced cell death. ..
- Stetler R, Cao G, Gao Y, Zhang F, Wang S, Weng Z, et al. Hsp27 protects against ischemic brain injury via attenuation of a novel stress-response cascade upstream of mitochondrial cell death signaling. J Neurosci. 2008;28:13038-55 pubmed publisher..Based on these findings, we conclude that overexpression of Hsp27 confers long-lasting neuroprotection against ischemic brain injury via a previously unexplored association and inhibition of ASK1 kinase signaling. ..
- Matsuzawa A, Saegusa K, Noguchi T, Sadamitsu C, Nishitoh H, Nagai S, et al. ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity. Nat Immunol. 2005;6:587-92 pubmed..Our data demonstrate that the reactive oxygen species-dependent TRAF6-ASK1-p38 axis is crucial for TLR4-mediated mammalian innate immunity. ..
- Nishitoh H, Kadowaki H, Nagai A, Maruyama T, Yokota T, Fukutomi H, et al. ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1. Genes Dev. 2008;22:1451-64 pubmed publisher..These findings demonstrate that ER stress-induced ASK1 activation, which is triggered by the specific interaction of Derlin-1 with SOD1(mut), is crucial for disease progression of familial ALS. ..
- Kim S, Kim T, Lee K. A novel function of peroxiredoxin 1 (Prx-1) in apoptosis signal-regulating kinase 1 (ASK1)-mediated signaling pathway. FEBS Lett. 2008;582:1913-8 pubmed publisher..In Prx-1 knockdown cells, ASK1, p38, and JNK were quickly activated, leading to apoptosis in response to H2O2. These findings suggest a negative role of Prx-1 in ASK1-induced apoptosis. ..