Eukaryotic translation elongation factor 1-alpha 1 inhibits p53 and p73 dependent apoptosis and chemotherapy sensitivity

PLoS One. 2013 Jun 14;8(6):e66436. doi: 10.1371/journal.pone.0066436. Print 2013.

Abstract

The p53 family of transcription factors is a key regulator of cell proliferation and death. In this report we identify the eukaryotic translation elongation factor 1-alpha 1 (eEF1A1) to be a novel p53 and p73 interacting protein. Previous studies have demonstrated that eEF1A1 has translation-independent roles in cancer. We report that overexpression of eEF1A1 specifically inhibits p53-, p73- and chemotherapy-induced apoptosis resulting in chemoresistance. Short-interfering RNA-mediated silencing of eEF1A1 increases chemosensitivity in cell lines bearing wild type p53, but not in p53 null cells. Furthermore, silencing of eEF1A1 partially rescues the chemoresistance observed in response to p53 or p73 knockdown, suggesting that eEF1A1 is a negative regulator of the pro-apoptotic function of p53 and p73. Thus, in the context of p53-family signaling, eEF1A1 has anti-apoptotic properties. These findings identify a novel mechanism of regulation of the p53 family of proteins by eEF1A1 providing additional insight into potential targets to sensitize tumors to chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis*
  • Camptothecin / pharmacology
  • Cisplatin / pharmacology
  • DNA-Binding Proteins / metabolism*
  • Doxorubicin / pharmacology
  • Drug Resistance, Neoplasm
  • Etoposide / pharmacology
  • Gene Expression
  • Gene Knockdown Techniques
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Nuclear Proteins / metabolism*
  • Peptide Elongation Factor 1 / physiology*
  • RNA, Small Interfering / genetics
  • Tumor Protein p73
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Antineoplastic Agents
  • DNA-Binding Proteins
  • EEF1A1 protein, human
  • Nuclear Proteins
  • Peptide Elongation Factor 1
  • RNA, Small Interfering
  • TP53 protein, human
  • TP73 protein, human
  • Tumor Protein p73
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Etoposide
  • Doxorubicin
  • Cisplatin
  • Camptothecin

Grant support

This work was supported by Canadian Cancer Society Research Institute (CCSRI #2010-700580) and a Canada Research Chair in Cancer Biology to MSI. AB is a recipient of the Hospital for Sick Children and Ministry of Education and Science (MEC) of Spain Scholarships. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.