Functional interaction between a RARE and an AP-2 binding site in the regulation of the human HOX A4 gene promoter

被引:39
作者
Doerksen, LF [1 ]
Bhattacharya, A [1 ]
Kannan, F [1 ]
Pratt, D [1 ]
Tainsky, MA [1 ]
机构
[1] UNIV TEXAS,MD ANDERSON CANCER CTR,DEPT TUMOR BIOL,HOUSTON,TX 77030
关键词
D O I
10.1093/nar/24.14.2849
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
HOX A genes are induced in a temporal fashion after retinoic acid (RA) treatment in non-N-ras-transformed PA-1 human teratcarcinoma cells. However, in N-ras-transformed PA-1 cells, RA-induced expression of HOX A genes is delayed. The mRNA for the transcriptional activator AP-2 is overexpressed in these ras-transformed cells, but AP-2 transcriptional activity is inhibited relative to non ras-transformed PA-1 cells. Constitutive expression of AP-2 mimics the effect of ras by transforming cells and inhibiting differentiation in culture. We analyzed 4 kb of the human HOX A4 gene promoter and identified seven putative AP-2-binding sites in the DNA sequence, Transcription assays with variably sized HOX A4 promoter reporter constructs revealed that a 365 bp region of the promoter, -2950 to -3315 relative to the mRNA start, controls RA responsiveness and ras-mediated inhibition of HOX A4 activity. This region contains an AP-2 binding site and a RARE. Elimination of the AP-2 site by site-directed mutagenesis demonstrated that the AP-2 site is involved in RA-mediated transcriptional activation of the human HOX A4 promoter in combination with the RA receptor response element (RARE). In N-ras-transformed cells, low HOX A4 promoter activity results from ras inhibition of AP-2 transactivation.
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页码:2849 / 2856
页数:8
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