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The human protein p53 regulates the response to DNA damage by binding specific regions of DNA and activating transcription of genes involved in the cell cycle and in cell death. It is also often found in a mutated, inactive form in tumor cells, and is thought to play a key role in the development of many cancers. Understanding how the activity of p53 is controlled may be an important step toward developing cancer treatments involving the conversion of the inactive form found in tumors to the active form.
The C-terminal region of p53 is thought to control the activity of the protein, as this region inhibits specific binding of p53 to DNA and must be modified or removed to allow full transcriptional activity. Exactly how this works, however, is unclear. A popular hypothesis has been that binding of the unmodified C-terminal region to other parts of the protein causes a structural change that is incompatible with specific DNA binding. However, as reported in the September issue of Nature Structural Biology (Vol. 8, No. 9, pages 756-760) by Arrowsmith and coworkers at the University of Toronto, this hypothesis appears to be incorrect. Using nuclear magnetic resonance (NMR), these authors show that the inactive and active forms of p53, with and without the C-terminal region, have the same structure. Surprisingly, the C-terminal region does not appear to interact with other parts of the protein or induce structural changes. Researchers interested in activating the p53 found in tumor cells may now have to reevaluate and investigate further the natural regulation mechanisms of this protein. Drs. Ahn and Prives further discuss the background and implications of this study in a related News and Views article (pages 730-732). Contact:
Dr. C. H. Arrowsmith
Ontario Cancer Institute
Dept. of Medical Biophysics
Div. of Mol. & Structural Biology
University of Toronto
610 University Ave.
Room 7-714
Toronto, Ontario M5G 2M9
Canada Dr. Carol Prives
Columbia University
Biological Sciences
818A Fairchild Center, M.C. 2422
1212 Amsterdam Avenue
New York, NY 10027 (C) Nature Structural Biology press release.
Message posted by: Trevor M. D'Souza
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