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J Biol Chem, Vol. 274, Issue 22, 15883-15891, May 28, 1999

Activation of the Murine Dihydrofolate Reductase Promoter by E2F1
A REQUIREMENT FOR CBP RECRUITMENT

Christopher J. Fry, Angela Pearson^¶, Erik Malinowski, Stephanie M. Bartley, Jack Greenblatt^¶, and Peggy J. Farnham

From the  McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, Wisconsin 53706 and the ^¶ Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario M5G 1L6, Canada

The E2F family of heterodimeric transcription factors plays an important role in the regulation of gene expression at the G₁/S phase transition of the mammalian cell cycle. Previously, we have demonstrated that cell cycle regulation of murine dihydrofolate reductase (dhfr) expression requires E2F-mediated activation of the dhfr promoter in S phase. To investigate the mechanism by which E2F activates an authentic E2F-regulated promoter, we precisely replaced the E2F binding site in the dhfr promoter with a Gal4 binding site. Using Gal4-E2F1 derivatives, we found that E2F1 amino acids 409-437 contain a potent core transactivation domain. Functional analysis of the E2F1 core domain demonstrated that replacement of phenylalanine residues 413, 425, and 429 with alanine reduces both transcriptional activation of the dhfr promoter and protein-protein interactions with CBP, transcription factor (TF) IIH, and TATA-binding protein (TBP). However, additional amino acid substitutions for phenylalanine 429 demonstrated a strong correlation between activation of the dhfr promoter and binding of CBP, but not TFIIH or TBP. Finally, transactivator bypass experiments indicated that direct recruitment of CBP is sufficient for activation of the dhfr promoter. Therefore, we suggest that recruitment of CBP is one mechanism by which E2F activates the dhfr promoter.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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