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We speculated that mutations in the autoinhibitory domain of CKI\u03b4\/\u03f5 might upregulate CKI\u03b4\/\u03f5 activity and hence Wnt signaling and increase the risk of adenomatous polyps and colon cancer. Exons encoding the CKI\u03f5 and CKI\u03b4 regulatory domains were sequenced from DNA obtained from individuals with adenomatous polyps and a family history of colon cancer unaffected by familial adenomatous polyposis or hereditary nonpolyposis colorectal cancer (HNPCC). A CKI\u03b4 missense mutation, changing a highly conserved residue, Arg324, to His (R324H), was found in an individual with large and multiple polyps diagnosed at a relatively young age. Two findings indicate that this mutation is biologically active. First, ectopic ventral expression of CKI\u03b4(R324H) in <jats:italic>Xenopus<\/jats:italic> embryos results in secondary axis formation with an additional distinctive phenotype (altered morphological movements) similar to that seen with unregulated CKI\u03f5. Second, CKI\u03b4(R324H) is more potent than wildtype CKI\u03b4 in transformation of RKO colon cancer cells. Although the R324H mutation does not significantly change CKI\u03b4 kinase activity in an <jats:italic>in vitro<\/jats:italic> kinase assay or Wnt\/\u03b2\u2010catenin signal transduction as assessed by a \u03b2\u2010catenin reporter assay, it alters morphogenetic movements via a \u03b2\u2010catenin\u2010independent mechanism in early <jats:italic>Xenopus<\/jats:italic> development. This novel human CKI\u03b4 mutation may alter the physiological role and enhance the transforming ability of CKI\u03b4 through a Wnt\/\u03b2\u2010catenin independent mechanism and thereby influence colonic adenoma development. \u00a9 2006 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ijc.22368","type":"journal-article","created":{"date-parts":[[2006,11,27]],"date-time":"2006-11-27T23:28:19Z","timestamp":1164670099000},"page":"1005-1012","source":"Crossref","is-referenced-by-count":27,"title":["Disease\u2010associated casein kinase I \u03b4 mutation may promote adenomatous polyps formation via a Wnt\/\u03b2\u2010catenin independent mechanism"],"prefix":"10.1002","volume":"120","author":[{"given":"I\u2010Chun","family":"Tsai","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margaret","family":"Woolf","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deborah W.","family":"Neklason","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William W.","family":"Branford","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H. 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