Basic fibroblast growth factor decreases elastin gene transcription through an AP1/cAMP-response element hybrid site in the distal promoter.
Previous studies demonstrated that basic fibroblast growth factor (bFGF) decreases elastin gene transcription in pulmonary fibroblasts. In this study we pursue the identification of the element and the trans-acting factors responsible. Gel shift analyses show that bFGF increases protein binding to a sequence located at -564 to -558 base pairs (bp), which possesses homology to both AP1 and cAMP-response consensus elements yet displays a unique affinity for heterodimer binding. Site-directed mutation of the -564- to -558-bp sequence results in an increase in promoter activity and abrogates the effect of bFGF. Western blot analysis shows that bFGF induces a sustained increase in the steady-state levels of Fra 1, and co-transfection of a Fra 1 expression vector with an elastin promoter reporter construct results in an inhibition of elastin promoter activity. Overall the results suggest that bFGF represses elastin gene transcription by increasing the amount of the Fra 1 that subsequently binds to the -564- to -558-bp as a heterodimer with c-Jun to form an inhibitory complex. We propose that the identified bFGF response element can serve to down-regulate elastin transcription in elastogenic cells and, conversely, can serve to up-regulate elastogenesis in cells where endogenous bFGF signaling is attenuated or altered.
Rich
C B
CB
Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Fontanilla
M R
MR
Nugent
M
M
Foster
J A
JA
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D017931:DNA Primers; D019281:Dimerization; D015536:Down-Regulation; D004549:Elastin / Q000235:genetics*; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D016296:Mutagenesis; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*; D000099169:Fos-Related Antigen 1
D000242:Cyclic AMP; D017931:DNA Primers; D004549:Elastin; D016222:Fibroblast Growth Factor 2; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D000099169:Fos-Related Antigen 1