{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T08:27:55Z","timestamp":1791188875321,"version":"4.1.0"},"reference-count":27,"publisher":"National Academy of Sciences","issue":"52","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2008,12,30]]},"abstract":"<jats:p>Glycogen synthase kinase-3 (GSK-3) is a master regulator of growth and death in cardiac myocytes. GSK-3 is inactivated by hypertrophic stimuli through phosphorylation-dependent and -independent mechanisms. Inactivation of GSK-3 removes the negative constraint of GSK-3 on hypertrophy, thereby stimulating cardiac hypertrophy. N-terminal phosphorylation of the GSK-3 isoforms GSK-3\u03b1 and GSK-3\u03b2 by upstream kinases (e.g., Akt) is a major mechanism of GSK-3 inhibition. Nonetheless, its role in mediating cardiac hypertrophy and failure remains to be established. Here we evaluated the role of Serine(S)21 and S9 phosphorylation of GSK-3\u03b1 and GSK-3\u03b2 in the regulation of cardiac hypertrophy and function during pressure overload (PO), using GSK-3\u03b1 S21A knock-in (\u03b1KI) and GSK-3\u03b2 S9A knock-in (\u03b2KI) mice. Although inhibition of S9 phosphorylation during PO in the \u03b2KI mice attenuated hypertrophy and heart failure (HF), inhibition of S21 phosphorylation in the \u03b1KI mice unexpectedly promoted hypertrophy and HF. Inhibition of S21 phosphorylation in GSK-3\u03b1, but not of S9 phosphorylation in GSK-3\u03b2, caused phosphorylation and down-regulation of G1-cyclins, due to preferential localization of GSK-3\u03b1 in the nucleus, and suppressed E2F and markers of cell proliferation, including phosphorylated histone H3, under PO, thereby contributing to decreases in the total number of myocytes in the heart. Restoration of the E2F activity by injection of adenovirus harboring cyclin D1 with a nuclear localization signal attenuated HF under PO in the \u03b1KI mice. Collectively, our results reveal that whereas S9 phosphorylation of GSK-3\u03b2 mediates pathological hypertrophy, S21 phosphorylation of GSK-3\u03b1 plays a compensatory role during PO, in part by alleviating the negative constraint on the cell cycle machinery in cardiac myocytes.<\/jats:p>","DOI":"10.1073\/pnas.0808315106","type":"journal-article","created":{"date-parts":[[2008,12,23]],"date-time":"2008-12-23T21:48:53Z","timestamp":1230068933000},"page":"20900-20905","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":131,"title":["Distinct roles of GSK-3\u03b1 and GSK-3\u03b2 phosphorylation in the heart under pressure overload"],"prefix":"10.1073","volume":"105","author":[{"given":"Takahisa","family":"Matsuda","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiyong","family":"Zhai","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Maejima","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chull","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shumin","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, Newark, NJ 07103;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazumichi","family":"Goto","sequence":"additional","affiliation":[{"name":"Asubio Pharma Co Ltd, Biomedical Research Laboratories, Shimamoto, Osaka 618-8503, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromitsu","family":"Takagi","sequence":"additional","affiliation":[{"name":"Asubio Pharma Co Ltd, Biomedical Research Laboratories, Shimamoto, Osaka 618-8503, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mimi","family":"Tamamori-Adachi","sequence":"additional","affiliation":[{"name":"Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigetaka","family":"Kitajima","sequence":"additional","affiliation":[{"name":"Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junichi","family":"Sadoshima","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2008,12,30]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000018952.70505.F1"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.231619298"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000065442.64694.9F"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.103.5.670"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.107.160614"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000012567.95445.55"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI19906"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1517\/14728222.9.3.447"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2004.03.015"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0835895100"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000124977.59827.80"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.11.7.824"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M103166200"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000184684.88750.FE"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1156037"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600633"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000259560.39234.99"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.12.22.3499"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000049105.15329.1C"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2004.03.002"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.15.8801"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2005.02.025"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2007.03.002"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.102.047381"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2006.08.004"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00323.2006"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2006.8.1635"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0808315106","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T17:57:09Z","timestamp":1649786229000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0808315106"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,12,30]]},"references-count":27,"journal-issue":{"issue":"52","published-print":{"date-parts":[[2008,12,30]]}},"alternative-id":["10.1073\/pnas.0808315106"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0808315106","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,12,30]]},"assertion":[{"value":"2008-08-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2008-12-30","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}