Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 102, Issue 29, Pages 10188-10193Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0503068102
Keywords
Mdm2; p53; tumor suppressor; Trp-53; ubiquitination
Categories
Funding
- NCI NIH HHS [R01 CA100845, R01 CA061449, 5 T32 CA009370-23, T32 CA009370, CA100845, CA61449] Funding Source: Medline
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P53 is an unstable transcription factor that is mutated in a majority of human cancers. With a significant role in initiating cell elimination programs, a network has evolved to fine-tune P53 transcriptional output and prevent errant activation. Modifications of the C terminus have long been viewed as critical binary determinants of P53 stability or activation. However, these conclusions are based on in vitro transfection or biochemical analyses where the stoichiometries between P53 and its regulators are perturbed. Therefore, we tested the importance of the C-terminal regulatory region for P53 control in mice where the seven C-terminal lysines were changed to arginine (Trp-53(7KR)). Surprisingly, the homozygous mutant mice are viable and phenotypically normal. We have functionally characterized the mutant protein in both MEFs and thymocytes, revealing the unexpected result that Trp-53(7KR) exhibits a normal half-life and functions like WT P53 in cell cycle arrest and apoptosis, and in an E1A-ras xenograft tumor suppression assay. However, a significant difference is that P53(7KR) is activated more easily by DNA damage in thymus than WT P53. Importantly, although MEFs encoding WT P53 spontaneously emerge from crisis to become immortal in a 3T3 growth protocol, we do not observe any such escape with the P53(7KR) cells. We propose that the C-terminal modifications believed to be critical for proper P53 regulation are not essential, but contribute to a fine-tuning mechanism of homeostatic control in vivo.
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