FOXM1c transactivates the human c-myc promoter directly via the two TATA boxes P1 and P2

Abstract

FOXM1c transactivates the c-myc promoter via the P1 and P2 TATA boxes using a new mechanism. Whereas the P1 TATA box TATAATGC requires its sequence context to be FOXM1c responsive, the P2 TATA box TATAAAAG alone is sufficient to confer FOXM1c responsiveness to any minimal promoter. FOXM1c transactivates by binding to the TATA box as well as directly to TATA-binding protein, transcription factor IIB and transcription factor IIA. This new transactivation mechanism is clearly distinguished from the function of FOXM1c as a conventional transcription factor. The central domain of FOXM1c functions as an essential domain for activation via the TATA box, but as an inhibitory domain (retinoblastoma protein-independent transrepression domain and retinoblastoma protein-recruiting negative regulatory domain) for transactivation via conventional FOXM1c-binding sites. Each promoter with the P2 TATA box TATAAAAG is postulated to be transactivated by FOXM1c. This was demonstrated for the promoters of c-fos, hsp70 and histone H2B/a. A database search revealed almost 300 probable FOXM1c target genes, many of which function in proliferation and tumorigenesis. Accordingly, dominant-negative FOXM1c proteins reduced cell growth approximately threefold, demonstrating a proliferation-stimulating function for wild-type FOXM1c.