Cancer-associated p53 tetramerization domain mutants: quantitative analysis reveals a low threshold for tumor suppressor inactivation
The tumor suppressor p53, a 393-amino acid transcription factor, induces cell cycle arrest and apoptosis in response to genotoxic stress. Its inactivation via the mutation of its gene is a key step in tumor progression, and tetramer formation is critical for p53 post-translational modification and its ability to activate or repress the transcription of target genes vital in inhibiting tumor growth. About 50% of human tumors have TP53 gene mutations; most are missense ones that presumably lower the tumor suppressor activity of p53. In this study, we explored the effects of known tumor-derived missense mutations on the stability and oligomeric structure of p53; our comprehensive, quantitative analyses encompassed the tetramerization domain peptides representing 49 such substitutions in humans. Their effects on tetrameric structure were broad, and the stability of the mutant peptides varied widely ({Delta}T{sub m} = 4.8 {approx} -46.8 C). Because formation of a tetrameric structure is critical for protein-protein interactions, DNA binding, and the post-translational modification of p53, a small destabilization of the tetrameric structure could result in dysfunction of tumor suppressor activity. We suggest that the threshold for loss of tumor suppressor activity in terms of the disruption of the tetrameric structure of p53 could be extremely low. However, other properties of the tetramerization domain, such as electrostatic surface potential and its ability to bind partner proteins, also may be important.
- Research Organization:
- Brookhaven National Lab. (BNL), Upton, NY (United States)
- Sponsoring Organization:
- LABORATORY-DIRECTED RESEARCH AND DEVELOPMENT
- DOE Contract Number:
- DE-AC02-98CH10886
- OSTI ID:
- 1040574
- Report Number(s):
- BNL-93638-2011-JA; JBCHA3; R&D Project: PD-10-006; YN0100000; TRN: US201210%%750
- Journal Information:
- Journal of Biological Chemistry, Vol. 286, Issue 1; ISSN 0021-9258
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
60 APPLIED LIFE SCIENCES
AMINO ACIDS
APOPTOSIS
CELL CYCLE
DNA
ELECTROSTATICS
GENE MUTATIONS
GENES
INACTIVATION
MODIFICATIONS
MUTANTS
MUTATIONS
NEOPLASMS
PEPTIDES
PROTEINS
STABILITY
SURFACE POTENTIAL
TARGETS
TRANSCRIPTION FACTORS
p53 cancer mutations
transcription factor
protein stability
protein oligomerization
thermal denaturation