title: ITF-2 is disrupted via allelic loss of chromosome 18q21, and ITF-2B expression is lost at the adenoma-carcinoma transition.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Medicine II, University of Munich, Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Herbst
authors.forename: Guido T
authors.initials: GT
authors.lastname: Bommer
authors.forename: Lydia
authors.initials: L
authors.lastname: Kriegl
authors.forename: Andreas
authors.initials: A
authors.lastname: Jung
authors.forename: Andrea
authors.initials: A
authors.lastname: Behrens
authors.forename: Endy
authors.initials: E
authors.lastname: Csanadi
authors.forename: Markus
authors.initials: M
authors.lastname: Gerhard
authors.forename: Christian
authors.initials: C
authors.lastname: Bolz
authors.forename: Rainer
authors.initials: R
authors.lastname: Riesenberg
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Zimmermann
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dietmaier
authors.forename: Isabella
authors.initials: I
authors.lastname: Wolf
authors.forename: Thomas
authors.initials: T
authors.lastname: Brabletz
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.forename: Frank T
authors.initials: FT
authors.lastname: Kolligs
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000473:pathology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D000073940:Transcription Factor 4; D014157:Transcription Factors; C407909:TCF3 protein, human; C532096:TCF4 protein, human