The first intron of the human alpha2(I) collagen gene (COL1A2) contains a novel interferon-gamma responsive element.
Cell transfection assays have shown that several transcription factors can mediate interferon-gamma (INF-gamma) inhibition of the human alpha2(I) collagen gene (COL1A2) by binding distinct cis-acting elements in the proximal promoter. Recent transgenic work, on the other hand, has identified a strong repressor in the first intron of COL1A2 that includes a binding site for interferon regulatory factors (IRFs). Here we present evidence from cell transfection experiments indicating that this IRF-binding site (IF3) is a novel target of the pathways elicited by INF-gamma to blunt transcription from the COL1A2 promoter. First, we showed that INF-gamma stimulates the production of IRF-1 transcripts, as well as the formation of an IRF-1 containing complex at the FI3 element. Second, we demonstrated that IRF-1 over-expression inhibits COL1A2 promoter activity specifically through the action of FI3, in addition to decreasing the steady-state levels of the endogenous COL1A2 mRNA. Third, we documented that INF-gamma treatment of cultured fibroblasts increases binding of IRF-1 to FI3 in the endogenous COL1A2 gene. Together our findings further extend the list of transcription factors involved in INF-gamma inhibition of COL1A2 gene expression.
Tanaka
Shizuko
S
Laboratory of Genetics and Organogenesis, Research Division of the Hospital for Special Surgery, and Department Physiology and Biophysics at Weill Medical College of Cornell University, New York, NY 10021, USA.
Ramirez
Francesco
F
D000818:Animals; D003094:Collagen / Q000235:genetics* / Q000378:metabolism; D024042:Collagen Type I; D005786:Gene Expression Regulation; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D050836:Interferon Regulatory Factor-2 / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D007438:Introns; D051379:Mice; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D020218:Response Elements; D014158:Transcription, Genetic
D024042:Collagen Type I; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; D007371:Interferon-gamma; D003094:Collagen