The activating transcription factor 3 protein suppresses the oncogenic function of mutant p53 proteins

J Biol Chem. 2014 Mar 28;289(13):8947-59. doi: 10.1074/jbc.M113.503755. Epub 2014 Feb 19.


Mutant p53 proteins (mutp53) often acquire oncogenic activities, conferring drug resistance and/or promoting cancer cell migration and invasion. Although it has been well established that such a gain of function is mainly achieved through interaction with transcriptional regulators, thereby modulating cancer-associated gene expression, how the mutp53 function is regulated remains elusive. Here we report that activating transcription factor 3 (ATF3) bound common mutp53 (e.g. R175H and R273H) and, subsequently, suppressed their oncogenic activities. ATF3 repressed mutp53-induced NFKB2 expression and sensitized R175H-expressing cancer cells to cisplatin and etoposide treatments. Moreover, ATF3 appeared to suppress R175H- and R273H-mediated cancer cell migration and invasion as a consequence of preventing the transcription factor p63 from inactivation by mutp53. Accordingly, ATF3 promoted the expression of the metastasis suppressor SHARP1 in mutp53-expressing cells. An ATF3 mutant devoid of the mutp53-binding domain failed to disrupt the mutp53-p63 binding and, thus, lost the activity to suppress mutp53-mediated migration, suggesting that ATF3 binds to mutp53 to suppress its oncogenic function. In line with these results, we found that down-regulation of ATF3 expression correlated with lymph node metastasis in TP53-mutated human lung cancer. We conclude that ATF3 can suppress mutp53 oncogenic function, thereby contributing to tumor suppression in TP53-mutated cancer.

Keywords: ATF3; Drug Resistance; Invasion; Lung Cancer; Migration; Mutant p53; p53.

Publication types

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

MeSH terms

  • Activating Transcription Factor 3 / metabolism*
  • Carcinogenesis / genetics*
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mutant Proteins / genetics*
  • Mutant Proteins / metabolism*
  • Mutation*
  • NF-kappa B p52 Subunit / metabolism
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Transcription Factors / metabolism
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Proteins / metabolism


  • ATF3 protein, human
  • Activating Transcription Factor 3
  • Mutant Proteins
  • NF-kappa B p52 Subunit
  • NFKB2 protein, human
  • TP63 protein, human
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins