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J. Biol. Chem., Vol. 276, Issue 30, 27999-28005, July 27, 2001

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Evidence for a Distinct Inhibitory Factor in the Regulation of p53 Functional Activity^*

Dmitri Wiederschain^§, JiJie Gu^§, and Zhi-Min Yuan^§¶

From the ^§ Department of Cancer Cell Biology, Harvard School of Public Health, Boston, Massachusetts 02115 and  The Program in Biological Sciences in Public Health, Graduate School of Arts and Sciences, Harvard University, Cambridge, Massachusetts 02138

Under normal conditions, tumor suppressor protein p53 exists in the cell in its latent form and is unable to function as a transcription factor. The allosteric model of p53 regulation postulates that the extreme portion of p53 carboxyl terminus (aa 364-393) binds to the core domain of the protein, thereby abrogating specific DNA binding in that region. In this study we propose an alternative mechanism of p53 functional regulation, which involves a separate molecule acting in trans to inhibit p53 transcriptional activity. Through the use of chimeric proteins of p53, p63 and p73, we show that the extreme COOH-terminal domain of p53 exerts a powerful and specific inhibitory effect on the p73- and p63-driven expression of a reporter gene. Moreover, fusion of p53 extreme COOH terminus to a completely unrelated transcriptional activator Gal4-VP16 also results in significant inhibition of transactivation activity. Since p73, p63, or Gal4-VP16 cannot associate with any part of the p53 molecule, we conclude that p53(aa 364-393) represses transcriptional activity of chimeric proteins and p53 itself through the binding of external negative modulator(s) in that region and not by the allosteric mechanism of regulation. In accordance with the "distinct inhibitor" hypothesis, the activity of wild type p53 is substantially increased by overexpression of chimeric proteins bearing p53(aa 364-393), which might be due to the competitive removal of transcriptional inhibitor(s). Our findings provide the basis for the identification of such negative modulators of p53 transcriptional activity.

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