A c-fos/Estrogen Receptor Fusion Protein Promotes Cell Cycle Progression and Proliferation of Human Cancer Cell Lines

Abstract

c-fos is the prototypic member of a family of transcription factors that regulate many cellular processes, including proliferation. c-fos heterodimerizes with jun family members to form the AP-1 transcription factor complex which binds specific DNA recognition elements in the promoters of many genes. Following rapid induction in response to serum or growth factors, c-fos regulates expression of downstream target genes involved in cellular proliferation. Although much work has focused on activation of cell cycle regulatory genes by c-fos, less is known about negative regulation of gene expression by this transcription factor. The cyclin-dependent kinase (cdk) inhibitor p21^Cip1/WAF1 is a negative regulator of cdk activity, thereby impeding cell cycle progression. By sequence analysis, we identified a putative AP-1 element in the p21^Cip1/WAF1 promoter. To investigate how this site regulated p21^Cip1/WAF1 expression and mitigate external effects on c-fos expression, we used a c-fos/estrogen receptor (c-fosER) fusion construct in which this transcription factor is conditionally activated by estradiol. In the presence of estradiol, c-fosER downregulated p21^Cip1/WAF1 promoter activity. This inhibition was dependent on the putative AP-1 site. Activation of c-fosER induced cell cycle progression and proliferation in a manner similar to serum stimulation. We concluded that activation of c-fosER mediated transcriptional inhibition of p21^Cip1/WAF1 through a previously uncharacterized AP-1 site, revealing an important role for c-fos in negative control of cell cycle regulatory genes.