The ZFHX3 (ATBF1) transcription factor induces PDGFRB, which activates ATM in the cytoplasm to protect cerebellar neurons from oxidative stress

Kim, TS, Kawaguchi, M, Suzuki, M, Jung, CG, Asai, K, Shibamoto, Y, Lavin, MF, Khanna, KK and Miura, Y (2010) The ZFHX3 (ATBF1) transcription factor induces PDGFRB, which activates ATM in the cytoplasm to protect cerebellar neurons from oxidative stress. DMM Disease Models and Mechanisms, 3 11-12: 752-762. doi:10.1242/dmm.004689

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Author Kim, TS
Kawaguchi, M
Suzuki, M
Jung, CG
Asai, K
Shibamoto, Y
Lavin, MF
Khanna, KK
Miura, Y
Title The ZFHX3 (ATBF1) transcription factor induces PDGFRB, which activates ATM in the cytoplasm to protect cerebellar neurons from oxidative stress
Journal name DMM Disease Models and Mechanisms   Check publisher's open access policy
ISSN 1754-8403
1754-8411
Publication date 2010-11
Sub-type Article (original research)
DOI 10.1242/dmm.004689
Open Access Status DOI
Volume 3
Issue 11-12
Start page 752
End page 762
Total pages 11
Place of publication Cambridge, United Kingdom
Publisher The Company of Biologists
Collection year 2011
Language eng
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.
Keyword Ataxia-telangiectasia
Growth-factor
Atrial-fibrillation
Gastric-cancer
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
Official 2011 Collection
 
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Created: Sun, 05 Dec 2010, 00:14:24 EST