{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T17:59:48Z","timestamp":1792519188744,"version":"4.5.0"},"reference-count":49,"publisher":"The Company of Biologists","issue":"11-12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2010,10,28]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n               <jats:p>Ataxia telangiectasia (A-T) is a neurodegenerative disease caused by mutations in the large serine-threonine kinase ATM. A-T patients suffer from degeneration of the cerebellum and show abnormal elevation of serum alpha-fetoprotein. Here, we report a novel signaling pathway that links ATM via cAMP-responsive-element-binding protein (CREB) to the transcription factor ZFHX3 (also known as ATBF1), which in turn promotes survival of neurons by inducing expression of platelet-derived growth factor receptor \u03b2 (PDGFRB). Notably, AG1433, an inhibitor of PDGFRB, suppressed the activation of ATM under oxidative stress, whereas AG1433 did not inhibit the response of ATM to genotoxic stress by X-ray irradiation. Thus, the activity of a membrane-bound tyrosine kinase is required to trigger the activation of ATM in oxidative stress, independent of the response to genotoxic stress. Kainic acid stimulation induced activation of ATM in the cerebral cortex, hippocampus and deep cerebellar nuclei (DCN), predominately in the cytoplasm in the absence of induction of \u03b3-H2AX (a marker of DNA double-strand breaks). The activation of ATM in the cytoplasm might play a role in autophagy in protection of neurons against oxidative stress. It is important to consider DCN of the cerebellum in the etiology of A-T, because these neurons are directly innervated by Purkinje cells, which are progressively lost in A-T.<\/jats:p>","DOI":"10.1242\/dmm.004689","type":"journal-article","created":{"date-parts":[[2010,9,28]],"date-time":"2010-09-28T04:35:56Z","timestamp":1285648556000},"page":"752-762","source":"Crossref","is-referenced-by-count":65,"title":["The ZFHX3 (ATBF1) transcription factor induces PDGFRB, which activates ATM in the cytoplasm to protect cerebellar neurons from oxidative stress"],"prefix":"10.1242","volume":"3","author":[{"given":"Tae-Sun","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Molecular Neurobiology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, 467-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Kawaguchi","sequence":"additional","affiliation":[{"name":"Department of Pathology, Niigata Rosai Hospital, Touncho, Joetsu, Niigata, 942-8502, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuko","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Molecular Neurobiology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, 467-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cha-Gyun","family":"Jung","sequence":"additional","affiliation":[{"name":"National Institute for Longevity Sciences, Obu, Aichi, 474-0031, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiyofumi","family":"Asai","sequence":"additional","affiliation":[{"name":"Department of Molecular Neurobiology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, 467-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuta","family":"Shibamoto","sequence":"additional","affiliation":[{"name":"Department of Radiology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, 467-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin F.","family":"Lavin","sequence":"additional","affiliation":[{"name":"Queensland Institute of Medical Research and University of Queensland Centre for Clinical Research, Brisbane 4029, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kum Kum","family":"Khanna","sequence":"additional","affiliation":[{"name":"Queensland Institute of Medical Research and University of Queensland Centre for Clinical Research, Brisbane 4029, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaka","family":"Miura","sequence":"additional","affiliation":[{"name":"Department of Molecular Neurobiology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, 467-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042513150079500_b1-0030752","doi-asserted-by":"crossref","first-page":"4153","DOI":"10.1073\/pnas.0913860107","article-title":"ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS","volume":"107","author":"Alexander","year":"2010","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021042513150079500_b2-0030752","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.1002\/ajmg.a.31853","article-title":"Ataxia-telangiectasia: mild neurological presentation despite null ATM mutation and severe cellular phenotype","volume":"143A","author":"Alterman","year":"2007","journal-title":"Am. J. Med. Genet"},{"key":"2021042513150079500_b3-0030752","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/0012-1606(84)90316-6","article-title":"Retinoic acid induces neuronal differentiation of a cloned human embryonal carcinoma cell line in vitro","volume":"103","author":"Andrews","year":"1984","journal-title":"Dev Biol"},{"key":"2021042513150079500_b4-0030752","first-page":"147","article-title":"Pluripotent embryonal carcinoma clones derived from the human teratocarcinoma cell line Tera-2. Differentiation in vivo and in vitro","volume":"50","author":"Andrews","year":"1984","journal-title":"Lab Invest"},{"key":"2021042513150079500_b5-0030752","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/nature01368","article-title":"DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation","volume":"421","author":"Bakkenist","year":"2003","journal-title":"Nature"},{"key":"2021042513150079500_b6-0030752","doi-asserted-by":"crossref","first-page":"1674","DOI":"10.1126\/science.281.5383.1674","article-title":"Enhanced phosphorylation of p53 by ATM in response to DNA damage","volume":"281","author":"Banin","year":"1998","journal-title":"Science"},{"key":"2021042513150079500_b7-0030752","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/S0092-8674(00)80086-0","article-title":"Atm-deficient mice: a paradigm of ataxia telangiectasia","volume":"86","author":"Barlow","year":"1996","journal-title":"Cell"},{"key":"2021042513150079500_b8-0030752","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1038\/ng.416","article-title":"Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry","volume":"41","author":"Benjamin","year":"2009","journal-title":"Nat Genet"},{"key":"2021042513150079500_b9-0030752","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1111\/j.1471-4159.2006.04254.x","article-title":"Constitutive expression and cytoplasmic compartmentalization of ATM protein in differentiated human neuron-like SH-SY5Y cells","volume":"100","author":"Boehrs","year":"2007","journal-title":"J Neurochem"},{"key":"2021042513150079500_b10-0030752","doi-asserted-by":"crossref","first-page":"22355","DOI":"10.1074\/jbc.M002259200","article-title":"The oxidative DNA lesion 8,5\u2032-(S)-cyclo-2\u2019-deoxyadenosine is repaired by the nucleotide excision repair pathway and blocks gene expression in mammalian cells","volume":"275","author":"Brooks","year":"2000","journal-title":"J Biol Chem"},{"key":"2021042513150079500_b11-0030752","doi-asserted-by":"crossref","first-page":"e1000319","DOI":"10.1371\/journal.pgen.1000319","article-title":"A genome-wide association study identifies novel and functionally related susceptibility Loci for Kawasaki disease","volume":"5","author":"Burgner","year":"2009","journal-title":"PLoS Genet"},{"key":"2021042513150079500_b12-0030752","doi-asserted-by":"crossref","first-page":"2555","DOI":"10.1073\/pnas.82.9.2555","article-title":"Identification and characterization of the human type II collagen gene (COL2A1)","volume":"82","author":"Cheah","year":"1985","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021042513150079500_b13-0030752","doi-asserted-by":"crossref","first-page":"39527","DOI":"10.1074\/jbc.M304423200","article-title":"Activation of p53 by oxidative stress involves platelet-derived growth factor-beta receptor-mediated ataxia telangiectasia mutated (ATM) kinase activation","volume":"278","author":"Chen","year":"2003","journal-title":"J Biol Chem"},{"key":"2021042513150079500_b14-0030752","doi-asserted-by":"crossref","first-page":"11453","DOI":"10.1523\/JNEUROSCI.23-36-11453.2003","article-title":"Oxidative stress is responsible for deficient survival and dendritogenesis in purkinje neurons from ataxia-telangiectasia mutated mutant mice","volume":"23","author":"Chen","year":"2003","journal-title":"J Neurosci"},{"key":"2021042513150079500_b15-0030752","doi-asserted-by":"crossref","first-page":"4355","DOI":"10.1158\/1078-0432.CCR-07-0619","article-title":"Genetic alterations of the ATBF1 gene in gastric cancer","volume":"13","author":"Cho","year":"2007","journal-title":"Clin Cancer Res"},{"key":"2021042513150079500_b16-0030752","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1126\/science.7901908","article-title":"Oxidative stress, glutamate, and neurodegenerative disorders","volume":"262","author":"Coyle","year":"1993","journal-title":"Science"},{"key":"2021042513150079500_b17-0030752","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/nsmb1090","article-title":"Two-step activation of ATM by DNA and the Mre11-Rad50-Nbs1 complex","volume":"13","author":"Dupre","year":"2006","journal-title":"Nat Struct Mol Biol"},{"key":"2021042513150079500_b18-0030752","doi-asserted-by":"crossref","first-page":"16577","DOI":"10.1074\/jbc.M609628200","article-title":"Activation of the kinase activity of ATM by retinoic acid is required for CREB-dependent differentiation of neuroblastoma cells","volume":"282","author":"Fernandes","year":"2007","journal-title":"J Biol Chem"},{"key":"2021042513150079500_b19-0030752","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1016\/j.dnarep.2007.06.011","article-title":"ATM, the Mre11\/Rad50\/Nbs1 complex, and topoisomerase I are concentrated in the nucleus of Purkinje neurons in the juvenile human brain","volume":"6","author":"Gorodetsky","year":"2007","journal-title":"DNA Rep"},{"key":"2021042513150079500_b20-0030752","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1038\/ng.417","article-title":"A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke","volume":"41","author":"Gudbjartsson","year":"2009","journal-title":"Nat Genet"},{"key":"2021042513150079500_b21-0030752","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1111\/j.1471-4159.2006.03922.x","article-title":"Mouse brains deficient in neuronal PDGF receptor-beta develop normally but are vulnerable to injury","volume":"98","author":"Ishii","year":"2006","journal-title":"J Neurochem"},{"key":"2021042513150079500_b22-0030752","doi-asserted-by":"crossref","first-page":"5137","DOI":"10.1242\/dev.02098","article-title":"Homeotic factor ATBF1 induces the cell cycle arrest associated with neuronal differentiation","volume":"132","author":"Jung","year":"2005","journal-title":"Development"},{"key":"2021042513150079500_b23-0030752","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/BF00304551","article-title":"Assignment of the structural gene coding for albumin to human chromosome 4","volume":"62","author":"Kao","year":"1982","journal-title":"Hum Genet"},{"key":"2021042513150079500_b24-0030752","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1038\/sj.onc.1204160","article-title":"Alpha-fetoprotein producing gastric cancer lacks transcription factor ATBF1","volume":"20","author":"Kataoka","year":"2001","journal-title":"Oncogene"},{"key":"2021042513150079500_b25-0030752","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1038\/85798","article-title":"DNA double-strand breaks: signaling, repair and the cancer connection","volume":"27","author":"Khanna","year":"2001","journal-title":"Nat Genet"},{"key":"2021042513150079500_b26-0030752","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1111\/j.1365-2559.2008.02980.x","article-title":"Down-regulation of ATBF1 is a major inactivating mechanism in hepatocellular carcinoma","volume":"52","author":"Kim","year":"2008","journal-title":"Histopathology"},{"key":"2021042513150079500_b27-0030752","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/S0006-8993(99)01813-2","article-title":"ATM immunolocalization in mouse neuronal endosomes: implications for ataxia-telangiectasia","volume":"842","author":"Kuljis","year":"1999","journal-title":"Brain Res"},{"key":"2021042513150079500_b28-0030752","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/nature05453","article-title":"Genome-wide atlas of gene expression in the adult mouse brain","volume":"445","author":"Lein","year":"2007","journal-title":"Nature"},{"key":"2021042513150079500_b29-0030752","doi-asserted-by":"crossref","first-page":"2091","DOI":"10.1016\/j.cub.2009.10.039","article-title":"Cytoplasmic ATM in neurons modulates synaptic function","volume":"19","author":"Li","year":"2009","journal-title":"Curr Biol"},{"key":"2021042513150079500_b30-0030752","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1096\/fasebj.10.9.8801179","article-title":"Retinoids and Hox genes","volume":"10","author":"Marshall","year":"1996","journal-title":"FASEB J"},{"key":"2021042513150079500_b31-0030752","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1126\/science.1140321","article-title":"ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage","volume":"316","author":"Matsuoka","year":"2007","journal-title":"Science"},{"key":"2021042513150079500_b32-0030752","doi-asserted-by":"crossref","first-page":"26840","DOI":"10.1074\/jbc.270.45.26840","article-title":"Cloning and characterization of an ATBF1 isoform that expresses in a neuronal differentiation-dependent manner","volume":"270","author":"Miura","year":"1995","journal-title":"J Biol Chem"},{"key":"2021042513150079500_b33-0030752","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1111\/j.1348-0421.2004.tb03491.x","article-title":"Susceptibility to killer T cells of gastric cancer cells enhanced by Mitomycin-C involves induction of ATBF1 and activation of p21 (Waf1\/Cip1) promoter","volume":"48","author":"Miura","year":"2004","journal-title":"Microbiol Immunol"},{"key":"2021042513150079500_b34-0030752","doi-asserted-by":"crossref","first-page":"6041","DOI":"10.1128\/MCB.11.12.6041","article-title":"A human alpha-fetoprotein enhancer-binding protein, ATBF1, contains four homeodomains and seventeen zinc fingers","volume":"11","author":"Morinaga","year":"1991","journal-title":"Mol Cell Biol"},{"key":"2021042513150079500_b35-0030752","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1083\/jcb.200809125","article-title":"Parkin is recruited selectively to impaired mitochondria and promotes their autophagy","volume":"183","author":"Narendra","year":"2008","journal-title":"J Cell Biol"},{"key":"2021042513150079500_b36-0030752","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/0006-8993(74)90640-4","article-title":"Kainic acid: a powerful neurotoxic analogue of glutamate","volume":"77","author":"Olney","year":"1974","journal-title":"Brain Res"},{"key":"2021042513150079500_b37-0030752","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1172\/JCI116429","article-title":"Tissue localization of beta receptors for platelet-derived growth factor and platelet-derived growth factor B chain during wound repair in humans","volume":"91","author":"Reuterdahl","year":"1993","journal-title":"J Clin Invest"},{"key":"2021042513150079500_b38-0030752","first-page":"14","article-title":"Cell culture methods and induction of differentiatin of embryonal carcinoma cell lines","volume-title":"Teratocarcinomas and Embryonic Stem Cells a Practical Approach","author":"Rudnicki","year":"1987"},{"key":"2021042513150079500_b39-0030752","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1126\/science.7792600","article-title":"A single ataxia telangiectasia gene with a product similar to PI-3 kinase","volume":"268","author":"Savitsky","year":"1995","journal-title":"Science"},{"key":"2021042513150079500_b40-0030752","doi-asserted-by":"crossref","first-page":"5898","DOI":"10.1073\/pnas.0307718101","article-title":"Direct regulation of CREB transcriptional activity by ATM in response to genotoxic stress","volume":"101","author":"Shi","year":"2004","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021042513150079500_b41-0030752","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/S0092-8674(00)80416-X","article-title":"DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2","volume":"91","author":"Shieh","year":"1997","journal-title":"Cell"},{"key":"2021042513150079500_b42-0030752","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/nrc1011","article-title":"ATM and related protein kinases: safeguarding genome integrity","volume":"3","author":"Shiloh","year":"2003","journal-title":"Nat Rev Cancer"},{"key":"2021042513150079500_b43-0030752","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/ng1528","article-title":"Frequent somatic mutations of the transcription factor ATBF1 in human prostate cancer","volume":"37","author":"Sun","year":"2005","journal-title":"Nat Genet"},{"key":"2021042513150079500_b44-0030752","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/0378-1119(84)90001-5","article-title":"Tandem arrangement of the albumin and alpha-fetoprotein genes in the human genome","volume":"32","author":"Urano","year":"1984","journal-title":"Gene"},{"key":"2021042513150079500_b45-0030752","doi-asserted-by":"crossref","first-page":"214","DOI":"10.4161\/auto.5369","article-title":"An autophagic mechanism is involved in apoptotic death of rat striatal neurons induced by the non-N-methyl-D-aspartate receptor agonist kainic acid","volume":"4","author":"Wang","year":"2008","journal-title":"Autophagy"},{"key":"2021042513150079500_b46-0030752","doi-asserted-by":"crossref","first-page":"1988","DOI":"10.1128\/MCB.01442-07","article-title":"Chromatin-bound p53 anchors activated Smads and the mSin3A corepressor to confer transforming-growth-factor-beta-mediated transcription repression","volume":"28","author":"Wilkinson","year":"2008","journal-title":"Mol Cell Biol"},{"key":"2021042513150079500_b47-0030752","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1128\/MCB.14.2.1395","article-title":"ATBF1, a multiple-homeodomain zinc finger protein, selectively down-regulates AT-rich elements of the human alpha-fetoprotein gene","volume":"14","author":"Yasuda","year":"1994","journal-title":"Mol Cell Biol"},{"key":"2021042513150079500_b48-0030752","doi-asserted-by":"crossref","first-page":"16693","DOI":"10.1074\/jbc.M109.010769","article-title":"Regulation of platelet-derived growth factor receptor function by integrin-associated cell surface transglutaminase","volume":"284","author":"Zemskov","year":"2009","journal-title":"J Biol Chem"},{"key":"2021042513150079500_b49-0030752","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1038\/ng859","article-title":"c-fos regulates neuronal excitability and survival","volume":"30","author":"Zhang","year":"2002","journal-title":"Nat Genet"}],"container-title":["Disease Models &amp; Mechanisms"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/3\/11-12\/752\/1618851\/752.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/3\/11-12\/752\/1618851\/752.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,25]],"date-time":"2021-04-25T14:46:02Z","timestamp":1619361962000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dmm\/article\/3\/11-12\/752\/20213\/The-ZFHX3-ATBF1-transcription-factor-induces"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,10,28]]},"references-count":49,"journal-issue":{"issue":"11-12","published-print":{"date-parts":[[2010,10,28]]}},"URL":"https:\/\/doi.org\/10.1242\/dmm.004689","relation":{},"ISSN":["1754-8411","1754-8403"],"issn-type":[{"value":"1754-8411","type":"electronic"},{"value":"1754-8403","type":"print"}],"subject":[],"published":{"date-parts":[[2010,10,28]]}}}