title: Suppression of colonic polyposis by homeoprotein CDX2 through its nontranscriptional function that stabilizes p27Kip1.
abstract: Caudal-related homeoprotein CDX2 is expressed in intestinal epithelial cells, in which it is essential for their development and differentiation. A tumor suppressor function is suggested by evidence that CDX2 levels are decreased in human colon cancer specimens and that an inactivating mutation of Cdx2 in Apc(Δ716) mice markedly increases the incidence of colonic polyps. In this study, we investigated roles for transcriptional and nontranscriptional functions of CDX2 in suppression of colonic tumorigenesis. Mutagenic analysis of CDX2 revealed that loss of function stabilizes CDK inhibitor p27Kip1 by a nontranscriptional but homeodomain-dependent mechanism that inhibits cyclin E-CDK2 activity and blocks G0/G1-S progression in colon cancer cells. p27Kip1 stabilization was mediated by an inhibition of ubiquitylation-dependent proteolysis associated with decreased phosphorylation of Thr187 in p27Kip1. siRNA-mediated knockdown of p27Kip1 relieved the decrease in cyclin E-CDK2 activity and S-phase cell fraction elicited by CDX2 expression. Together, these results implicate a nontranscriptional function of CDX2 in tumor suppression mediated by p27Kip1 stabilization. Up to approximately 75% of low-CDX2 human colon cancer lesions show reduced levels of p27Kip1, whereas approximately 68% of high-CDX2 lesions retain expression of p27Kip1. These results show that low levels of CDX2 accelerate colon tumorigenesis by reducing p27Kip1 levels.
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, Kyoto University, and Laboratory of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Aoki
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Kakizaki
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sakashita
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Manabe
authors.forename: Masahiro
authors.initials: M
authors.lastname: Aoki
authors.forename: Makoto M
authors.initials: MM
authors.lastname: Taketo
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000071616:CDX2 Transcription Factor; D002453:Cell Cycle / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003111:Colonic Polyps / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D014158:Transcription, Genetic; D054875:Ubiquitination
chemical_list: C436291:CDKN1B protein, human; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D016213:Cyclins; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2