{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T14:28:51Z","timestamp":1770992931903,"version":"3.50.1"},"reference-count":41,"publisher":"Rockefeller University Press","issue":"6","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2008,6,16]]},"abstract":"<jats:p>The SCFFBW7 ubiquitin ligase degrades proteins involved in cell division, growth, and differentiation and is commonly mutated in cancers. The Fbw7 locus encodes three protein isoforms that occupy distinct subcellular localizations, suggesting that each has unique functions. We used gene targeting to create isoform-specific Fbw7-null mutations in human cells and found that the nucleoplasmic Fbw7\u03b1 isoform accounts for almost all Fbw7 activity toward cyclin E, c-Myc, and sterol regulatory element binding protein 1. Cyclin E sensitivity to Fbw7 varies during the cell cycle, and this correlates with changes in cyclin E\u2013cyclin-dependent kinase 2 (CDK2)\u2013specific activity, cyclin E autophosphorylation, and CDK2 inhibitory phosphorylation. These data suggest that oscillations in cyclin E\u2013CDK2-specific activity during the cell cycle regulate the timing of cyclin E degradation. Moreover, they highlight the utility of adeno-associated virus\u2013mediated gene targeting in functional analyses of complex loci.<\/jats:p>","DOI":"10.1083\/jcb.200802076","type":"journal-article","created":{"date-parts":[[2008,6,16]],"date-time":"2008-06-16T21:42:19Z","timestamp":1213652539000},"page":"913-920","update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":102,"title":["Isoform- and cell cycle\u2013dependent substrate degradation by the Fbw7 ubiquitin ligase"],"prefix":"10.1083","volume":"181","author":[{"given":"Jonathan E.","family":"Grim","sequence":"first","affiliation":[{"name":"1Divisions of Clinical Research"},{"name":"2Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109"}]},{"given":"Michael P.","family":"Gustafson","sequence":"additional","affiliation":[{"name":"1Divisions of Clinical Research"},{"name":"3Mayo Clinic, Rochester, MN 55905"}]},{"given":"Roli K.","family":"Hirata","sequence":"additional","affiliation":[{"name":"4Division of Hematology, University of Washington School of Medicine, Seattle, WA 98109"}]},{"given":"Amanda C.","family":"Hagar","sequence":"additional","affiliation":[{"name":"1Divisions of Clinical Research"},{"name":"2Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109"}]},{"given":"Jherek","family":"Swanger","sequence":"additional","affiliation":[{"name":"1Divisions of Clinical Research"},{"name":"2Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109"}]},{"given":"Markus","family":"Welcker","sequence":"additional","affiliation":[{"name":"1Divisions of Clinical Research"},{"name":"2Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109"}]},{"given":"Harry C.","family":"Hwang","sequence":"additional","affiliation":[{"name":"1Divisions of Clinical Research"},{"name":"2Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109"}]},{"given":"Johan","family":"Ericsson","sequence":"additional","affiliation":[{"name":"5Ludwig Institute for Cancer Research, 751 24 Uppsala, Sweden"}]},{"given":"David W.","family":"Russell","sequence":"additional","affiliation":[{"name":"4Division of Hematology, University of Washington School of Medicine, Seattle, WA 98109"}]},{"given":"Bruce E.","family":"Clurman","sequence":"additional","affiliation":[{"name":"1Divisions of Clinical Research"},{"name":"2Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109"}]}],"member":"291","published-online":{"date-parts":[[2008,6,16]]},"reference":[{"key":"2023072223391838100_BIB1","doi-asserted-by":"crossref","first-page":"9006","DOI":"10.1158\/0008-5472.CAN-07-1320","volume":"67","year":"2007","journal-title":"Cancer Res."},{"key":"2023072223391838100_BIB2","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1016\/j.molcel.2007.06.013","volume":"27","year":"2007","journal-title":"Mol. 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