Differentiated embryo-chondrocyte expressed gene 1 regulates p53-dependent cell survival versus cell death through macrophage inhibitory cytokine-1

Proc Natl Acad Sci U S A. 2012 Jul 10;109(28):11300-5. doi: 10.1073/pnas.1203185109. Epub 2012 Jun 21.


Activation of p53 upon DNA damage induces an array of target genes, leading to cell cycle arrest and/or apoptosis. However, the mechanism by which the cell fate is controlled by p53 remains to be clarified. Previously, we showed that DEC1, a basic helix-loop-helix transcription factor and a target of p53, is capable of inducing cell cycle arrest and mediating DNA damage-induced premature senescence. Here, we found that ectopic expression of DEC1 inhibits, whereas knockdown of DEC1 enhances, DNA damage-induced cell death. Surprisingly, we showed that the anti-cell-death activity of DEC1 is p53 dependent, but DEC1 does not directly modulate p53 expression. Instead, we showed that DEC1 inhibits the ability of p53 to induce macrophage inhibitory cytokine-1 (MIC-1), but not other prosurvival/proapoptotic targets, including p21 and Puma. Importantly, we showed that upon binding to their respective response elements on the MIC-1 promoter, DEC1 and p53 physically interact on the MIC-1 promoter via the basic helix-loop-helix domain in DEC1 and the tetramerization domain in p53, which likely weakens the DNA-binding activity of p53 to the MIC-1 promoter. Finally, we found that depletion of MIC-1 abrogates the ability of DEC1 to attenuate DNA damage-induced cell death. Together, we hypothesize that DEC1 controls the response of p53-dependent cell survival vs. cell death to a stress signal through MIC-1.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Apoptosis
  • Cell Death
  • Cell Differentiation
  • Cell Survival
  • Cellular Senescence
  • DNA Damage
  • Genes, p53*
  • Growth Differentiation Factor 15 / metabolism*
  • Humans
  • Promoter Regions, Genetic
  • Tretinoin / metabolism
  • Tumor Suppressor Protein p53 / physiology*
  • Tumor Suppressor Proteins / physiology*


  • DELEC1 protein, human
  • GDF15 protein, human
  • Growth Differentiation Factor 15
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Tretinoin