Novel Link of Anti-apoptotic ATF3 with Pro-apoptotic CTMP in the Ischemic Brain

Chien Yu Huang, Jin Jer Chen, Jui Sheng Wu, Hsin Da Tsai, Heng Lin, Yu Ting Yan, Chung-Yi Hsu, Yuan-Soon Ho, Teng Nan Lin

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Activating transcription factor 3 (ATF3) is a stress-induced transcription factor with diverse functions under disease states in multiple cell types. ATF3 has neuroprotective action against cerebral ischemia, which may involve caspase 3. However, the molecular mechanisms underlying ATF3 regulation of apoptosis are largely unknown. Here, we used gain- and loss-of-function and rescue approaches to demonstrate ATF3 attenuating hypoxic neuronal apoptosis. As well, the protective effect of ATF3 was mediated by downregulation of carboxyl-terminal modulator protein (CTMP), a pro-apoptotic factor that inhibits the anti-apoptotic Akt/PKB cascade. ATF3 (1) downregulated the mRNA and protein levels of CTMP; (2) its temporal expression pattern was reciprocal to that of CTMP; and (3) nuclear localization suggested that ATF3 may regulate CTMP transcription following hypoxic insult. Reporter assays demonstrated that ATF3 suppressed CTMP transcription, whereas ATF3 fusion with VP16, converting ATF3 to transcriptional activator, boosted CTMP transcription. By contrast, NF-κB increased CTMP transcription, and degradation-resistant IκBα decreased CTMP transcription. ChIP assays further confirmed that binding of ATF3 to the ATF/CREB site hindered NF-κB binding to the CTMP promoter, which repressed CTMP expression. Furthermore, CTMP siRNA treatment reduced hypoxic neuronal apoptosis by increasing p-Akt (Ser473) levels and leaving the upstream ATF3 level unchanged. We have identified an endogenous neuroprotective ATF3→CTMP signal cascade that may be a therapeutic target for reducing ischemic brain injury.

Original languageEnglish
Pages (from-to)543-557
Number of pages15
JournalMolecular Neurobiology
Volume51
Issue number2
DOIs
Publication statusPublished - 2015

Fingerprint

Activating Transcription Factor 3
Brain
Proteins
Apoptosis
Activating Transcription Factor 1
Down-Regulation
Apoptosis Regulatory Proteins
Nuclear Proteins
Brain Ischemia

Keywords

  • Akt
  • Apoptosis
  • CREB
  • Gene regulation
  • NF-κB

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Novel Link of Anti-apoptotic ATF3 with Pro-apoptotic CTMP in the Ischemic Brain. / Huang, Chien Yu; Chen, Jin Jer; Wu, Jui Sheng; Tsai, Hsin Da; Lin, Heng; Yan, Yu Ting; Hsu, Chung-Yi; Ho, Yuan-Soon; Lin, Teng Nan.

In: Molecular Neurobiology, Vol. 51, No. 2, 2015, p. 543-557.

Research output: Contribution to journalArticle

Huang, Chien Yu ; Chen, Jin Jer ; Wu, Jui Sheng ; Tsai, Hsin Da ; Lin, Heng ; Yan, Yu Ting ; Hsu, Chung-Yi ; Ho, Yuan-Soon ; Lin, Teng Nan. / Novel Link of Anti-apoptotic ATF3 with Pro-apoptotic CTMP in the Ischemic Brain. In: Molecular Neurobiology. 2015 ; Vol. 51, No. 2. pp. 543-557.
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