{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T21:22:18Z","timestamp":1780521738856,"version":"3.54.1"},"reference-count":48,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,1,24]],"date-time":"2023-01-24T00:00:00Z","timestamp":1674518400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Minister of Science and Technology and Academia Sinica, Taiwan (TNL)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Activating transcription factor 3 (ATF3) is a stress-induced transcription factor and a familiar neuronal marker for nerve injury. This factor has been shown to protect neurons from hypoxic insult in vitro by suppressing carboxyl-terminal modulator protein (CTMP) transcription, and indirectly activating the anti-apoptotic Akt\/PKB cascade. Despite prior studies in vitro, whether this neuroprotective pathway also exists in the brain in vivo after ischemic insult remains to be determined. In the present study, we showed a rapid and marked induction of ATF3 mRNA throughout ischemia-reperfusion in a middle cerebral artery (MCA) occlusion model. Although the level of CTMP mRNA was quickly induced upon ischemia, its level showed only a mild increase after reperfusion. With the gain-of-function approach, both pre- and post-ischemic administration of Ad-ATF3 ameliorated brain infarct and neurological deficits. Whereas, with the loss-of-function approach, ATF3 knockout (KO) mice showed bigger infarct and worse functional outcome after ischemia. In addition, these congenital defects were rescued upon reintroducing ATF3 to the brain of KO mice. ATF3 overexpression led to a lower level of CTMP and a higher level of p-Akt(473) in the ischemic brain. On the contrary, ATF3 KO resulted in upregulation of CTMP and downregulation of p-Akt(473) instead. Furthermore, post-ischemic CTMP siRNA knockdown led to smaller infarct and better behaviors. CTMP siRNA knockdown increased the level of p-Akt(473), but did not alter the ATF3 level in the ischemic brain, upholding the ATF3\u2192CTMP signal cascade. In summary, our proof-of-principle experiments support the existence of neuroprotective ATF3\u2192CTMP signal cascade regulating the ischemic brain. Furthermore, these results suggest the therapeutic potential for both ATF3 overexpression and CTMP knockdown for stroke treatment.<\/jats:p>","DOI":"10.3390\/ijms24032306","type":"journal-article","created":{"date-parts":[[2023,1,25]],"date-time":"2023-01-25T03:53:18Z","timestamp":1674618798000},"page":"2306","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Activating Transcription Factor 3 Diminishes Ischemic Cerebral Infarct and Behavioral Deficit by Downregulating Carboxyl-Terminal Modulator Protein"],"prefix":"10.3390","volume":"24","author":[{"given":"Mei-Han","family":"Kao","sequence":"first","affiliation":[{"name":"Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei 11529, Taiwan"},{"name":"Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5643-1227","authenticated-orcid":false,"given":"Chien-Yu","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wai-Mui","family":"Cheung","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Ting","family":"Yan","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Jer","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3649-6680","authenticated-orcid":false,"given":"Yuan-Soon","family":"Ho","sequence":"additional","affiliation":[{"name":"School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5632-2733","authenticated-orcid":false,"given":"Chung Y.","family":"Hsu","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404327, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4009-0798","authenticated-orcid":false,"given":"Teng-Nan","family":"Lin","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,24]]},"reference":[{"key":"ref_1","first-page":"321","article-title":"ATF3 and stress responses","volume":"7","author":"Hai","year":"1999","journal-title":"Gene Expr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.1101\/gad.3.12b.2083","article-title":"Transcription factor ATF cDNA clones: An extensive family of leucine zipper proteins able to selectively form DNA-binding heterodimers","volume":"3","author":"Hai","year":"1989","journal-title":"Genes Dev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3727\/105221610X12819686555015","article-title":"ATF3, a hub of the cellular adaptive-response network, in the pathogenesis of diseases: Is modulation of inflammation a unifying component?","volume":"15","author":"Hai","year":"2010","journal-title":"Gene Expr. 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