Because of its expression in numerous cells, the herpes simplex virus thymidine kinase promoter (HSV-TK) is one of the best characterized promoters. Using the HSV-TK promoter as a model system, we have defined a new mode of E2F-1 transcriptional activation which utilizes the N-terminal region of E2F-1. We demonstrate that E2F-1 strongly activated HSV-TK, but in the absence of consensus E2F DNA elements. Nonetheless, E2F-1 could bind to GC-rich elements, which were conclusively identified in classic studies of HSV-TK as SP-1 sites. Second, the transcriptional activation of HSV-TK required the entire E2F-1 protein, including the N-terminal 89 amino acids. In contrast, the N-terminal 89 amino acids of E2F-1 were dispensable for transcriptional activation through consensus E2F sites. Third, we demonstrated that S phase entry is not sufficient for activation of HSV-TK by E2F-1, while the activation through consensus E2F sites is strictly linked to the cell cycle. Taken together, the activation of HSV-TK by E2F-1 proceeds by a different mechanism directed in part through the N-terminal region of E2F-1 and may be uncoupled from the known cell cycle regulatory role.

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