Chaperoning of mutant p53 protein by wild-type p53 protein causes hypoxic tumor regression

Rajan Gogna, Esha Madan, Periannan Kuppusamy, Uttam Pati

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Mutant (Mt) p53 abrogates tumor suppression functions of wild-type (WT) p53 through mutant-specific, gain-of-function effects, and patients bearing Mt p53 are chemoresistant. The dominant negative effect of p53 mutants results from their aggregation propensity which causes co-aggregation of WT p53. We explored the mechanism of p53 inactivation in hypoxia and hypothesized whether WT p53 could rescue Mt p53 in hypoxic tumors. WT p53 exists in mutant conformation in hypoxic core of MCF-7 solid tumors, and its conformation is oxygen-dependent. Under simulated hypoxia in cells, WT p53 undergoes conformational change in acquiring mutant conformation. An in vivo chaperone assay shows that WT p53 functions as a molecular chaperone in rescuing conformational and structural p53 mutants in cancer cells both at the transcription and proteome levels. WT p53 chaperone therapy is further shown to cause significant regression of tumor xenografts through reconversion of the mutant phenotype to wild-type p53. The chaperone function of WT p53 is directly linked to the induction of apoptosis in both cancer cells and tumor xenografts. As oncogenic p53 mutants are linked to chemoresistance in hypoxic tumors, p53 chaperone therapy will introduce new dimensions to existing cancer therapeutics. We propose that in cancer cells, WT p53 chaperoning may either exist as a cellular event to potentially reverse the dominant negative effect of its oncogenic mutants or to stabilize yet unidentified factors.

Original languageEnglish (US)
Pages (from-to)2907-2914
Number of pages8
JournalJournal of Biological Chemistry
Volume287
Issue number4
DOIs
StatePublished - Jan 20 2012
Externally publishedYes

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Mutant Proteins
Tumors
Conformations
Neoplasms
Proteins
Cells
Heterografts
Bearings (structural)
Agglomeration
Molecular Chaperones
Proteome
Transcription
Assays
Cell Hypoxia
Apoptosis
Oxygen
Therapeutics
Phenotype

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Chaperoning of mutant p53 protein by wild-type p53 protein causes hypoxic tumor regression. / Gogna, Rajan; Madan, Esha; Kuppusamy, Periannan; Pati, Uttam.

In: Journal of Biological Chemistry, Vol. 287, No. 4, 20.01.2012, p. 2907-2914.

Research output: Contribution to journalArticle

Gogna, Rajan ; Madan, Esha ; Kuppusamy, Periannan ; Pati, Uttam. / Chaperoning of mutant p53 protein by wild-type p53 protein causes hypoxic tumor regression. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 4. pp. 2907-2914.
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