Inhibition of stress-inducible kinase pathways by tumorigenic mutant p53

Mol Cell Biol. 2003 Jan;23(1):322-34. doi: 10.1128/MCB.23.1.322-334.2003.

Abstract

More than 50% of human cancers contain p53 gene mutations and as a result accumulate altered forms of the full-length p53 protein. Although certain tumor types expressing mutant p53 protein have a poor prognostic process, the precise role of mutant p53 protein in highly malignant tumor cells is not well defined. Some p53 mutants, but not wild-type p53, are shown here to interact with Daxx, a Fas-binding protein that activates stress-inducible kinase pathways. Interaction of Daxx with p53 is highly dependent upon the specific mutation of p53. Tumorigenic mutants of p53 bind to Daxx and inhibit Daxx-dependent activation of the apoptosis signal-regulating kinase 1 stress-inducible kinases and Jun NH(2)-terminal kinase. Mutant p53 forms complexes with Daxx in cells, and consequently, mutant p53 is able to rescue cells from Daxx-dependent inhibition of proliferation. Thus, the accumulation of mutant p53 in tumor cells may contribute to tumorigenesis by inhibiting stress-inducible kinase pathways.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Apoptosis / physiology
  • Binding Sites
  • Carcinogenicity Tests
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Survival / genetics
  • Cells, Cultured
  • Co-Repressor Proteins
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 5
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism*
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism
  • Molecular Chaperones
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Stress, Physiological
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism*
  • Two-Hybrid System Techniques
  • fas Receptor / genetics
  • fas Receptor / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Co-Repressor Proteins
  • DAXX protein, human
  • Intracellular Signaling Peptides and Proteins
  • Molecular Chaperones
  • Nuclear Proteins
  • Tumor Suppressor Protein p53
  • fas Receptor
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 5
  • MAP Kinase Kinase Kinases
  • MAP3K5 protein, human