We have previously shown that FOXM1c transactivates the c-myc P1 and P2 promoters via their TATA-boxes by a new transactivation mechanism, namely by directly binding to the P1 and P2 TATA-boxes and to TBP, TFIIA, and TFIIB. We now confirm this surprising mechanism by demonstrating that FOXM1c transactivates the human c-myc P1 and P2 promoters synergistically with Sp1, a transcription factor known to bind and transactivate these two promoters. This synergism requires the PI or P2 TATA-boxes as well as the respective Sp1-binding sites. Moreover FOXM1c binds directly to Sp1. Cooperative DNA binding, if it should occur, is not sufficient for synergism of Sp1 and FOXM1c at P1, but their contacts to multiple components of the basal transcription complex (TFIID, TFIIA, TFIIB) seem to be essential. However, FOXM1c does not synergize with Sp1 if it transactivates via its conventional binding site. (c) 2006 Elsevier Inc. All rights reserved.