{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:38:19Z","timestamp":1790674699569,"version":"4.1.0"},"reference-count":49,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2013,10,24]],"date-time":"2013-10-24T00:00:00Z","timestamp":1382572800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"NIH MERIT","award":["R37 AA11085"],"award-info":[{"award-number":["R37 AA11085"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2014,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Prenatal ethanol exposure causes persistent neurodevelopmental deficits by inducing apoptosis within neuronal progenitors including the neural crest. The cellular signaling events underlying this apoptosis are unclear. Using an established chick embryo model, we previously identified ethanol's activation of calmodulin\u2010dependent protein kinase II (CaMKII) as a crucial early step in this pathway. Here, we report that CaMKII is pro\u2010apoptotic because it mediates the loss of transcriptionally active \u03b2\u2010catenin, which normally provides trophic support to these cells. \u03b2\u2010catenin over\u2010expression normalized cell survival in ethanol's presence. CaMKII inhibition similarly restored \u03b2\u2010catenin content and transcriptional activity within ethanol\u2010treated cells and prevented their cell death. In contrast, inhibition of alternative effectors known to destabilize \u03b2\u2010catenin, including glycogen synthase kinase\u20103\u03b2, Protein Kinase C, JNK, and calpain, failed to normalize cell survival and \u03b2\u2010catenin activity in ethanol's presence. Importantly, we found that purified CaMKII can directly phosphorylate \u03b2\u2010catenin. Using targeted mutagenesis we identified CaMKII phosphorylation sites within human \u03b2\u2010catenin at T332, T472, and S552. This is the first demonstration that \u03b2\u2010catenin is a phosphorylation target of CaMKII and represents a novel mechanism by which calcium signals could regulate \u03b2\u2010catenin\u2010dependent transcription. These results inform ethanol's neurotoxicity and offer unexpected insights into other neurodevelopmental and neurodegenerative disorders having dysregulated calcium or \u03b2\u2010catenin signaling.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc12464-fig-0008-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><jats:p>We proposed that ethanol initiates apoptosis in early neuroprogenitors through an intracellular calcium transient that activates CaMKII, which in turn destabilizes transcriptionally\u2010active beta\u2010catenin, perhaps through direct phosphorylation at Thr332, Thr472 and Ser552. This represents a novel mechanism of calcium\u2010modulation of Wnt signaling and of ethanol's neurotoxicity.<\/jats:p>","DOI":"10.1111\/jnc.12464","type":"journal-article","created":{"date-parts":[[2013,10,12]],"date-time":"2013-10-12T01:34:59Z","timestamp":1381541699000},"page":"523-535","source":"Crossref","is-referenced-by-count":56,"title":["CaMKII represses transcriptionally active \u03b2\u2010catenin to mediate acute ethanol neurodegeneration and can phosphorylate \u03b2\u2010catenin"],"prefix":"10.1111","volume":"128","author":[{"given":"George R.","family":"Flentke","sequence":"first","affiliation":[{"name":"Department of Nutritional Sciences University of Wisconsin\u2010Madison Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Garic","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences University of Wisconsin\u2010Madison Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcos","family":"Hernandez","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences University of Wisconsin\u2010Madison Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences University of Wisconsin\u2010Madison Madison Wisconsin USA"},{"name":"Waisman Center for Neurodevelopmental Disorders University of Wisconsin\u2010Madison Madison Wisconsin 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