title: The ZFHX3 (ATBF1) transcription factor induces PDGFRB, which activates ATM in the cytoplasm to protect cerebellar neurons from oxidative stress.
abstract: 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 β (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 γ-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.
authors.affiliation: Department of Molecular Neurobiology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, 467-8601, Japan.
authors.forename: Tae-Sun
authors.initials: TS
authors.lastname: Kim
authors.forename: Makoto
authors.initials: M
authors.lastname: Kawaguchi
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Suzuki
authors.forename: Cha-Gyun
authors.initials: CG
authors.lastname: Jung
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Asai
authors.forename: Yuta
authors.initials: Y
authors.lastname: Shibamoto
authors.forename: Martin F
authors.initials: MF
authors.lastname: Lavin
authors.forename: Kum Kum
authors.initials: KK
authors.lastname: Khanna
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Miura
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D015815:Cell Adhesion Molecules / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002531:Cerebellum / Q000166:cytology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000201:enzymology*; D019610:Cytoprotection / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D018384:Oxidative Stress / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism*
chemical_list: D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D025521:Tumor Suppressor Proteins; C489511:Zfhx3 protein, mouse; C071660:ZFHX3 protein, human; D014212:Tretinoin; D020797:Receptor, Platelet-Derived Growth Factor beta; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases