A widely expressed transcription factor with multiple DNA sequence specificity, CTCF, is localized at chromosome segment 16q22.1 within one of the smallest regions of overlap for common deletions in breast and prostate cancers.
The cellular protooncogene MYC encodes a nuclear transcription factor that is involved in regulating important cellular functions, including cell cycle progression, differentiation, and apoptosis. Dysregulated MYC expression appears critical to the development of various types of malignancies, and thus factors involved in regulating MYC expression may also play a key role in the pathogenesis of certain cancers. We have cloned one such MYC regulatory factor, termed CTCF, which is a highly evolutionarily conserved-11-zinc finger transcriptional factor possessing multiple DNA sequence specificity. CTCF binds to a number of important regulatory regions within the 5' noncoding sequence of the human MYC oncogene, and it can regulate its transcription in several experimental systems. CTCF mRNA is expressed in cells of multiple different lineages. Enforced ectopic expression of CTCF inhibits cell growth in culture. Southern blot analyses and fluorescence in situ hybridization (FISH) with normal human metaphase chromosomes showed that the human CTCF is a single-copy gene situated at chromosome locus 16q22. Cytogenetic studies have pointed out that chromosome abnormalities (deletions) at this locus frequently occur in many different human malignancies, suggesting the presence of one or more tumor suppressor genes in the region. To narrow down their localization, several loss of heterozygosity (LOH) studies of chromosome arm 16q in sporadic breast and prostate cancers have been carried out to define the most recurrent and smallest region(s) of overlap (SRO) for commonly deleted chromosome arm 16q material. For CTCF to be considered as a candidate tumor suppressor gene associated with tumorigenesis, it should localize within one of the SROs at 16q. Fine-mapping of CTCF has enabled us to assign the CTCF gene to about a 2 centiMorgan (cM) interval of 16q22.1 between the somatic cell hybrid breakpoints CY130(D) and CY4, which is between markers D16S186 (16AC16-101) and D16S496 (AFM214zg5). This relatively small region, containing the CTCF gene, overlaps the most frequently observed SROs for common chromosomal deletions found in sporadic breast and prostate tumors. In one of four analyzed paired DNA samples from primary breast cancer patients, we have detected a tumor-specific rearrangement of CTCF exons encoding the 11-zinc-finger domain. Therefore, taken together with other CTCF properties, localization of CTCF to a narrow cancer-associated chromosome region suggests that CTCF is a novel candidate tumor suppressor gene at 16q22.1.
Filippova
G N
GN
Molecular Medicine Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Lindblom
A
A
Meincke
L J
LJ
Klenova
E M
EM
Neiman
P E
PE
Collins
S J
SJ
Doggett
N A
NA
Lobanenkov
V V
VV
D001943:Breast Neoplasms / Q000235:genetics*; D000076246:CCCTC-Binding Factor; D002871:Chromosome Banding; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D005807:Genes, Overlapping; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics*; D012097:Repressor Proteins; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured
D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D014157:Transcription Factors