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CREB-binding Protein and p300/CBP-associated Factor Are Transcriptional Coactivators of the p53 Tumor Suppressor Protein¹

Department of Molecular Genetics, The Wistar Institute [D. M. S., N. H. C., E. S. S., M. C. L., L. C., S. L. B., T. D. H.], Programs in Biochemistry [D. M. S., N. H. C.] and Neuroscience [M. C. L.], and Department of Pathology and Laboratory Medicine [T. D. H.], University of Pennsylvania, Philadelphia, Pennsylvania 19104, and Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140 [E. M.]

The structurally related transcriptional coactivators p300 and CBP possess histone acetyltransferase activity and associate with P/CAF, which is also a histone acetyltransferase. CBP and p300 have properties of tumor suppressor proteins; their interaction with P/CAF is disrupted by the adenoviral E1A oncoprotein, and the genes encoding CBP and p300 are mutated in human cancer. We observed a physical interaction between the transactivation domain of the p53 tumor suppressor protein and CBP. Furthermore, CBP and P/CAF enhanced the ability of p53 to activate expression of the endogenous p21^cip1/waf1 gene, whereas E1A and dominant negative CBP mutants suppressed p53-dependent p21^cip1/waf1 expression. These studies link two tumor suppressor families and provide a framework for understanding the molecular mechanism by which p53 activates transcription.

¹ These studies were supported in part by a grant from the Council for Tobacco Research (to S. L. B. and T. D. H.), a NIH Training Grant (to D. M. S.), and a NIH Cancer Core Grant to the Wistar Institute.

² The first two authors contributed equally to this work.

³ To whom requests for reprints should be addressed, at the Wistar Institute, 3601 Spruce Sreet, Philadelphia, PA 19104-4268. E-mail: halazonetis@wista.wistar.upenn.edu.

Received 6/18/97. Accepted 7/17/97.

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