title: Tumor-associated zinc finger mutations in the CTCF transcription factor selectively alter tts DNA-binding specificity.
abstract: CTCF is a widely expressed 11-zinc finger (ZF) transcription factor that is involved in different aspects of gene regulation including promoter activation or repression, hormone-responsive gene silencing, methylation-dependent chromatin insulation, and genomic imprinting. Because CTCF targets include oncogenes and tumor suppressor genes, we screened over 100 human tumor samples for mutations that might disrupt CTCF activity. We did not observe any CTCF mutations leading to truncations/premature stops. Rather, in breast, prostate, and Wilms' tumors, we observed four different CTCF somatic missense mutations involving amino acids within the ZF domain. Each ZF mutation abrogated CTCF binding to a subset of target sites within the promoters/insulators of certain genes involved in regulating cell proliferation but did not alter binding to the regulatory sequences of other genes. These observations suggest that CTCF may represent a novel tumor suppressor gene that displays tumor-specific "change of function" rather than complete "loss of function."
authors.affiliation: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Galina N
authors.initials: GN
authors.lastname: Filippova
authors.forename: Chen-Feng
authors.initials: CF
authors.lastname: Qi
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Ulmer
authors.forename: James M
authors.initials: JM
authors.lastname: Moore
authors.forename: Michael D
authors.initials: MD
authors.lastname: Ward
authors.forename: Ying J
authors.initials: YJ
authors.lastname: Hu
authors.forename: Dmitri I
authors.initials: DI
authors.lastname: Loukinov
authors.forename: Elena M
authors.initials: EM
authors.lastname: Pugacheva
authors.forename: Elena M
authors.initials: EM
authors.lastname: Klenova
authors.forename: Paul E
authors.initials: PE
authors.lastname: Grundy
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Feinberg
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Cleton-Jansen
authors.forename: Elna W
authors.initials: EW
authors.lastname: Moerland
authors.forename: Cees J
authors.initials: CJ
authors.lastname: Cornelisse
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Akira
authors.initials: A
authors.lastname: Komiya
authors.forename: Annika
authors.initials: A
authors.lastname: Lindblom
authors.forename: Françoise
authors.initials: F
authors.lastname: Dorion-Bonnet
authors.forename: Paul E
authors.initials: PE
authors.lastname: Neiman
authors.forename: Herbert C
authors.initials: HC
authors.lastname: Morse
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Collins
authors.forename: Victor V
authors.initials: VV
authors.lastname: Lobanenkov
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D016147:Genes, Tumor Suppressor; D005914:Globins / Q000235:genetics; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009113:Muramidase / Q000235:genetics; D020125:Mutation, Missense; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D012097:Repressor Proteins; D013379:Substrate Specificity; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D009396:Wilms Tumor / Q000235:genetics / Q000378:metabolism; D016335:Zinc Fingers / Q000235:genetics*
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D005914:Globins; D009113:Muramidase