ATF CREB SITE MEDIATED TRANSCRIPTIONAL ACTIVATION AND P53 DEPENDENT REPRESSION OF THE CYCLIN-A PROMOTER/

Cyclin A is a pivotal regulatory protein which, in mammalian cells, is involved in the S phase of the cell cycle. Transcription of the human cyclin A gene is cell cycle regulated through tight control of its pr omoter. We have previously shown that the ATF/CREB site, present in th e cyclin A promoter, mediates transcriptional regulation by cAMP respo nsive element binding proteins. The main goal of the present study was to investigate whether this site is involved in transcriptional regul ation of the gene. We have constructed stable NIH-3T3 cell lines that express the luciferase reporter gene under the control of normal or mu tated versions of the cyclin A promoter. We show that the ATF/CREB is required to achieve maximal levels of transcription from the cyclin A promoter starting in late G1. We also show that down-regulation of the cyclin A promoter by p53 does not implicate a direct binding of p53 t o its cognate consensus sequence but occurs probably by interference w ith trans-activating factors. This result suggests that p53 can interf ere with transcription of the cyclin A gene, in the absence of a TATA sequence in the promoter.