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Molecular and Cellular Biology, May 1999, p. 3246-3256, Vol. 19, No. 5
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Cumulative Effect of Phosphorylation of pRB on Regulation of E2F Activity

Vivette D. Brown,1,2 Robert A. Phillips,1,2,dagger and Brenda L. Gallie1,2,*

Department of Molecular and Medical Genetics, University of Toronto,1 and Cancer and Blood Research, Hospital for Sick Children,2 Toronto, Ontario M5G 1X8, Canada

Received 26 October 1998/Returned for modification 25 November 1998/Accepted 3 February 1999

The product of the retinoblastoma susceptibility gene, pRB, is a nuclear phosphoprotein that controls cell growth by binding to and suppressing the activities of transcription factors such as the E2F family. Transactivation activity is inhibited when E2F is bound to hypophosphorylated pRB and released when pRB is phosphorylated by cyclin-dependent kinases (CDKs). To determine which of 16 potential CDK phosphorylation sites regulated the pRB-E2F interaction, mutant pRB proteins produced by site-directed mutagenesis were tested for the ability to suppress E2F-mediated transcription in a reporter chloramphenicol acetyltransferase assay. Surprisingly, no one CDK site regulated the interaction of pRB with E2F when E2F was bound to DNA. Instead, disruption of transcriptional repression resulted from accumulation of phosphate groups on the RB molecule.

* Corresponding author. Mailing address: The Hospital for Sick Children, 555 University Ave., Rm. 8124 Elm, Toronto, Ontario M5G 1X8, Canada. Phone: (416) 813-6530. Fax: (416) 813-8883. E-mail: rbbg{at}sickkids.on.ca.

dagger Present address: National Cancer Institute of Canada, Toronto, Ontario M4V 3B1, Canada.

Molecular and Cellular Biology, May 1999, p. 3246-3256, Vol. 19, No. 5
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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