PROMOTER FUNCTION AND STRUCTURE OF THE GROWTH FACTOR-INDUCIBLE IMMEDIATE EARLY GENE CYR61

cyr61 is an immediate early gene that is transcriptionally activated in 3T3 fibroblasts by serum, platelet-derived growth factor, fibroblast growth factor, and the tumor promoter TPA with kinetics similar to the induction of c-fos. cyr61 encodes a secreted protein that is associated with the cell surface and the extracellular matrix, and may play a role in cell-cell communication. We report here the complete nucleotide sequence of the mouse cyr61 gene, which contains four short introns. The transcription start site was mapped by S1 nuclease and primer extension analyses. A 2 kb 5' flanking DNA fragment functions as a serum-inducible promoter. This DNA fragment contains a poly(CA) sequence that can adopt the Z DNA form. In addition, it contains a sequence that resembles the serum response element (SRE) originally identified in the c-fos promoter. We show that deletion of the cyr61 SRE-like sequence abrogates serum inducibility. Furthermore, this SRE-like sequence is sufficient to confer serum and growth factor inducibility when linked to a basal promoter, and binds the 67 kD serum response factor in vitro. We conclude that the cyr61 SRE functions as a serum response element and may account for the coordinate activation of cyr61 and c-fos.