The p53 Pathway: Origins, Inactivation in Cancer, and Emerging Therapeutic Approaches

Annu Rev Biochem. 2016 Jun 2;85:375-404. doi: 10.1146/annurev-biochem-060815-014710. Epub 2016 May 4.

Abstract

Inactivation of the transcription factor p53, through either direct mutation or aberrations in one of its many regulatory pathways, is a hallmark of virtually every tumor. In recent years, screening for p53 activators and a better understanding of the molecular mechanisms of oncogenic perturbations of p53 function have opened up a host of novel avenues for therapeutic intervention in cancer: from the structure-guided design of chemical chaperones to restore the function of conformationally unstable p53 cancer mutants, to the development of potent antagonists of the negative regulators MDM2 and MDMX and other modulators of the p53 pathway for the treatment of cancers with wild-type p53. Some of these compounds have now moved from proof-of-concept studies into clinical trials, with prospects for further, personalized anticancer medicines. We trace the structural evolution of the p53 pathway, from germ-line surveillance in simple multicellular organisms to its pluripotential role in humans.

Keywords: cancer therapy; drug design; p53 family; protein evolution; signaling pathways; small-molecule stabilizers.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents, Alkylating / chemical synthesis
  • Antineoplastic Agents, Alkylating / therapeutic use*
  • Cell Cycle Proteins
  • Clinical Trials as Topic
  • Drug Design
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Molecular Docking Simulation
  • Molecular Targeted Therapy*
  • Mutation
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Protein Multimerization
  • Protein Structure, Secondary
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-mdm2 / chemistry
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Signal Transduction
  • Tumor Suppressor Protein p53 / agonists*
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Antineoplastic Agents, Alkylating
  • Cell Cycle Proteins
  • MDM4 protein, human
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2