title: A novel Ku70 function in colorectal homeostasis separate from nonhomologous end joining.
abstract: Ku70, a known nonhomologous end-joining (NHEJ) factor, also functions in tumor suppression, although this molecular mechanism remains uncharacterized. Previously, we showed that mice deficient for DNA ligase IV (Lig4), another key NHEJ factor, succumbed to aggressive lymphoma in the absence of tumor suppressor p53. However, the tumor phenotype is abrogated by the introduction of a hypomorphic mutant p53(R172P), which impaired p53-mediated apoptosis but not cell-cycle arrest. However, Lig4(-/-)p53(R172P) mice succumbed to severe diabetes. To further elucidate the role of NHEJ and p53-mediated apoptosis in vivo, we bred Ku70(-/-) p53(R172P) mice. Unexpectedly, these mice were free of diabetes, although 80% of the mutant mice had abnormally enlarged colons with pronounced inflammation. Remarkably, most of these mutant mice progressed to dysplasia, adenoma and adenocarcinoma; this is in contrast to the Lig4(-/-)p53(R172P) phenotype, strongly suggesting an NHEJ-independent function of Ku70. Significantly, our analyses of Ku70(-/-)p53(R172P) colonic epithelial cells show nuclear stabilization of β-catenin accompanied by higher expression of cyclin D1 and c-Myc in affected colon sections than in control samples. This is not due to the p53 mutation, as Ku70(-/-) mice share this phenotype. Our results not only unravel a novel function of Ku70 essential for colon homeostasis, but also establish an excellent in vivo model in which to study how chronic inflammation and abnormal cellular proliferation underlie tumorigenesis and tumor progression in the colon.
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: N
authors.initials: N
authors.lastname: Puebla-Osorio
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ojeda
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.affiliation: 1] Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA [2] The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
authors.forename: O
authors.initials: O
authors.lastname: Tavana
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 1] The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA [2] Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Ma
authors.affiliation: 1] Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA [2] The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Schluns
authors.affiliation: 1] Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA [2] The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Zhu
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D034961:Antigens, Nuclear / Q000502:physiology*; D063646:Carcinogenesis; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D003106:Colon / Q000276:immunology / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage; D059766:DNA End-Joining Repair; D004268:DNA-Binding Proteins / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D000072200:Ku Autoantigen; D051379:Mice; D018345:Mice, Knockout; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D060449:Wnt Signaling Pathway
chemical_list: D034961:Antigens, Nuclear; C530105:Ccnd1 protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D015850:Interleukin-6; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; C577686:interleukin-6, mouse; D019938:Cyclin D1; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen