ITF-2 is disrupted via allelic loss of chromosome 18q21, and ITF-2B expression is lost at the adenoma-carcinoma transition.

Herbst, A; Bommer, GT; Kriegl, L; Jung, A; Behrens, A; Csanadi, E; Gerhard, M; Bolz, C; Riesenberg, R; Zimmermann, W; Dietmaier, W; Wolf, I; Brabletz, T; Göke, B; Kolligs, FT

doi:10.1053/j.gastro.2009.04.049

journal article

Titel:: ITF-2 is disrupted via allelic loss of chromosome 18q21, and ITF-2B expression is lost at the adenoma-carcinoma transition.
Dokumenttyp:: Journal Article; Research Support, Non-U.S. Gov't
Autor(en):: Herbst, A; Bommer, GT; Kriegl, L; Jung, A; Behrens, A; Csanadi, E; Gerhard, M; Bolz, C; Riesenberg, R; Zimmermann, W; Dietmaier, W; Wolf, I; Brabletz, T; Göke, B; Kolligs, FT
Abstract:: BACKGROUND & AIMS: The ubiquitously expressed basic helix-loop-helix transcription factor ITF-2B has an important role in differentiation processes, and its transcription is regulated by beta-catenin. The ITF-2 gene is located in the chromosomal region 18q21; allelic loss of this locus occurs in 70% of colorectal cancers. We analyzed the expression, regulation, and function of ITF-2B in colorectal carcinogenesis. METHODS: The loss-of-heterozygosity (LOH) status of 18q21 and expression of ITF-2B were studied in colorectal carcinomas using polymerase chain reaction-based methods and immunohistochemistry. The biologic effects of ITF-2B were studied in colorectal cancer cells. Reporter gene assays and chromatin immunoprecipitation were utilized to analyze effects of ITF-2B on gene transcription. RESULTS: ITF-2B is strongly expressed in colon adenomas but frequently down-regulated in carcinomas because of LOH at 18q21. ITF-2B induces cell cycle arrest and regulates the expression of p21(Cip1) via newly identified E-boxes in the CDKN1A gene, independently of p53. Loss of ITF-2B expression correlates with loss of p21(Cip1) expression in primary colon carcinomas. CONCLUSIONS: Accumulation of mutations and allelic losses are driving forces of colorectal carcinogenesis. ITF-2B, which is up-regulated during early colorectal carcinogenesis because of loss of adenomatous polyposis coli, is a target for LOH on chromosome 18q, along with deleted in colorectal carcinoma and Smad4. This finding, along with the fact that ITF-2B is a regulator of the key cell cycle inhibitor p21(Cip1), indicates that ITF-2B is a tumor suppressor that has an important function at the adenoma to carcinoma transition.
Zeitschriftentitel:: Gastroenterology
Jahr:: 2009
Band / Volume:: 137
Heft / Issue:: 2
Seitenangaben Beitrag:: 639-48, 648.e1-9
Sprache:: eng
Volltext / DOI:: doi:10.1053/j.gastro.2009.04.049
PubMed:: http://view.ncbi.nlm.nih.gov/pubmed/19394332
Print-ISSN:: 0016-5085
TUM Einrichtung:: II. Medizinische Klinik und Poliklinik (Gastroenterologie)
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mediaTUM Gesamtbestand Einrichtungen Schools TUM School of Medicine and Health Departments Clinical Medicine Klinik und Poliklinik für Innere Medizin II, Gastroenterologie (Prof. Schmid)2009