Structure, sequence, and promoter analysis of human disabled-2 gene (DAB2)

被引:29
作者
Sheng, ZJ
He, JQ
Tuppen, JA
Sun, WP
Fazili, Z
Smith, ER
Dong, FB
Xu, XX
机构
[1] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA
[2] Emory Univ, Sch Med, Dept Biochem, Atlanta, GA 30322 USA
[3] Emory Univ, Sch Med, Winship Canc Ctr, Atlanta, GA 30322 USA
[4] Georgia Inst Technol, Sch Biol, Atlanta, GA 30332 USA
[5] Georgia Inst Technol, Inst Bioengn & Biosci, Atlanta, GA 30332 USA
关键词
D O I
10.1006/geno.2000.6383
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Disabled-2 (DAB2 for human and Dab2 for other species) is one of two mammalian orthologues of Drosophila Disabled. DAB2 exhibits properties of a tumor suppressor gene: the expression of DAB2 is eliminated in 85-95% of breast and ovarian tumors; homozygous deletions of the gene have been found in some of these tumors; and reintroduction of DAB2 expression suppresses tumorigenicity of carcinoma cells. To study the mechanisms of loss of expression and to detect possible mutations in tumors, we have investigated the genomic structure of the DAB2 gene. The complete DAB2 gene was identified and sequenced from four overlapping BAC clones found to contain the gene. Complement factor 9 (C9) gene was localized next to the DAB2 gene at the 3'-end of the BAC DNA fragments. The human DAB2 gene is about 35 kb in size and consists of 15 exons and 14 introns, producing an approximately 4-kb message. A spliced variant corresponding to mouse Dab2 p93 and a 3'-end spliced variant were also identified. The translation initiation site resides in the second exon, and the noncoding first exon is separated from the second exon by a 14-kb intron. The 420-bp sequence 5' of exon 1 contains a CpG island (39 CpG sites). This 420-bp putative promoter was found to contain the site for transcription initiation, identified by RNase protection assay, and is sufficient for active transcription in epithelial cells. The information about the gene structure of DAB2 will enable us to analyze possible mutations and the mechanisms of loss of DAB2 expression in tumors. (C) 2000 Academic Press.
引用
收藏
页码:381 / 386
页数:6
相关论文
共 27 条
[1]   Sequence, genomic structure, and chromosomal assignment of human DOC-2 [J].
Albertsen, HM ;
Smith, SA ;
Melis, R ;
Williams, B ;
Holik, P ;
Stevens, J ;
White, R .
GENOMICS, 1996, 33 (02) :207-213
[2]   PURIFICATION OF CPG ISLANDS USING A METHYLATED DNA-BINDING COLUMN [J].
CROSS, SH ;
CHARLTON, JA ;
NAN, XS ;
BIRD, AP .
NATURE GENETICS, 1994, 6 (03) :236-244
[3]   Disabled-2 inactivation is an early step in ovarian tumorigenicity [J].
Fazili, Z ;
Sun, WP ;
Mittelstaedt, S ;
Cohen, C ;
Xu, XX .
ONCOGENE, 1999, 18 (20) :3104-3113
[4]  
FAZILI Z, UNPUB DISABLED 2 GEN
[5]   Eukaryotic promoter recognition [J].
Fickett, JW ;
Hatzigeorgiou, AC .
GENOME RESEARCH, 1997, 7 (09) :861-878
[6]   THREONYL-TRANSFER RNA-SYNTHETASE GENE MAPS CLOSE TO LEUCYL-TRANSFER RNA-SYNTHETASE GENE ON HUMAN CHROMOSOME-5 [J].
GERKEN, SC ;
WASMUTH, JJ ;
ARFIN, SM .
SOMATIC CELL AND MOLECULAR GENETICS, 1986, 12 (05) :519-522
[7]   DROSOPHILA ABL TYROSINE KINASE IN EMBRYONIC CNS AXONS - A ROLE IN AXONOGENESIS IS REVEALED THROUGH DOSAGE-SENSITIVE INTERACTIONS WITH DISABLED [J].
GERTLER, FB ;
BENNETT, RL ;
CLARK, MJ ;
HOFFMANN, FM .
CELL, 1989, 58 (01) :103-113
[8]   DOSAGE-SENSITIVE MODIFIERS OF DROSOPHILA-ABL TYROSINE KINASE FUNCTION - PROSPERO, A REGULATOR OF AXONAL OUTGROWTH, AND DISABLED, A NOVEL TYROSINE KINASE SUBSTRATE [J].
GERTLER, FB ;
HILL, KK ;
CLARK, MJ ;
HOFFMANN, FM .
GENES & DEVELOPMENT, 1993, 7 (03) :441-453
[9]   Mouse disabled (mDab1): A Src binding protein implicated in neuronal development [J].
Howell, BW ;
Gertler, FB ;
Cooper, JA .
EMBO JOURNAL, 1997, 16 (01) :121-132
[10]   Neuronal position in the developing brain is regulated by mouse disabled-1 [J].
Howell, BW ;
Hawkes, R ;
Soriano, P ;
Cooper, JA .
NATURE, 1997, 389 (6652) :733-737