P53 STIMULATES TRANSCRIPTION FROM THE HUMAN TRANSFORMING GROWTH-FACTOR-ALPHA PROMOTER - A POTENTIAL GROWTH-STIMULATORY ROLE FOR P53

Physical and chemical agents can damage the genome, Part of the protec tive response to this damage is the increased expression of p53. p53, a transcription factor, controls the expression of genes, leading to c ell cycle arrest and apoptosis, Another protective mechanism is the pr oliferative response required to replace the damaged cells, This proli feration is likely to be signaled by growth factors. In this communica tion, we show that the transforming growth factor or (TGF-alpha) gene is a direct target for p53-mediated transcriptional activation, In a s table cell line containing an inducible p53 construct, p53 induction l eads to a threefold accumulation of the native TGF-alpha mRNA. In cotr ansfection assays using a TGF-alpha promoter reporter construct, we sh ow that expression of wild-type but not mutant p53 increases transcrip tional activity of the TGF-alpha promoter by approximately 2.5-fold. I n vitro, wild-type p53 binds to a consensus binding site found in the proximal portion of the promoter, and this sequence is necessary for t he p53 transcriptional response, Furthermore, this element confers p53 induction to the otherwise nonresponsive adenovirus major late promot er, In addition to these results, we found that the TGF-alpha promoter contains a nonconsensus but functional TATA box-binding protein-bindi ng site approximately 30 ttp upstream of the transcription start site. Although p53 can repress transcription from promoters containing a TA TA box, the nonconsensus TGF-alpha TATA motif is resistant to this eff ect, On the basis of these results, we propose that p53 may play a dua l role, which includes both the elimination of irreparably genetically damaged cells and the proliferative response necessary for their repl acement, in the response to physical-chemical damage.