Regulation of the p53-MDM2 pathway by 14-3-3 sigma and other proteins

Semin Cancer Biol. 2006 Jun;16(3):225-34. doi: 10.1016/j.semcancer.2006.03.009. Epub 2006 Apr 6.

Abstract

The 14-3-3 sigma (sigma) protein, a unique member of 14-3-3 family, is a negative regulator of the cell cycle and is induced by p53 to initiate cell cycle checkpoint control after DNA damage. Among the 14-3-3 family members, 14-3-3 sigma is uniquely induced by p53 and has a positive feedback effect on p53 activity in response to DNA damage. Although 14-3-3 sigma is linked to p53-regulated cell cycle checkpoint control, the detailed mechanisms of cell cycle regulation by 14-3-3 sigma remain unclear. Decreased expression of 14-3-3 sigma was reported in several types of carcinomas, suggesting that the negative regulatory role of 14-3-3 sigma in the cell cycle is compromised during tumorigenesis. Given the fact that p53's tumor suppressive function is lost in almost half of all human cancers and that 14-3-3 sigma's activity is linked to the p53 network, a perspective regarding the p53/14-3-3 sigma relationship is needed for cancer research. Here we discuss the mechanisms by which 14-3-3 sigma-stabilizes p53 with the hope that these insights may be applied to develop targeted therapeutic strategies for cancer treatment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • 14-3-3 Proteins
  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Biomarkers, Tumor / chemistry
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Cell Cycle Proteins / metabolism
  • DNA-Binding Proteins / metabolism
  • Endopeptidases / metabolism
  • Exonucleases / chemistry
  • Exonucleases / genetics
  • Exonucleases / metabolism*
  • Exoribonucleases
  • Gene Expression Regulation, Neoplastic / physiology*
  • Humans
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • PTEN Phosphohydrolase / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding / physiology
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • Repressor Proteins / metabolism
  • Signal Transduction / physiology*
  • Tripartite Motif-Containing Protein 28
  • Tumor Suppressor Protein p14ARF / metabolism
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Proteins / metabolism
  • Ubiquitin Thiolesterase
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitin-Specific Peptidase 7

Substances

  • 14-3-3 Proteins
  • Biomarkers, Tumor
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Neoplasm Proteins
  • PSMD10 protein, human
  • Proto-Oncogene Proteins
  • Repressor Proteins
  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • BRAP protein, human
  • Proto-Oncogene Proteins c-mdm2
  • TRIM28 protein, human
  • Tripartite Motif-Containing Protein 28
  • Ubiquitin-Protein Ligases
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Exonucleases
  • Exoribonucleases
  • SFN protein, human
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Endopeptidases
  • USP7 protein, human
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Peptidase 7
  • Proteasome Endopeptidase Complex