A short acidic motif in ARF guards against mitochondrial dysfunction and melanoma susceptibility

Nat Commun. 2014 Nov 5;5:5348. doi: 10.1038/ncomms6348.

Abstract

ARF is a small, highly basic protein that can be induced by oncogenic stimuli and exerts growth-inhibitory and tumour-suppressive activities through the activation of p53. Here we show that, in human melanocytes, ARF is cytoplasmic, constitutively expressed, and required for maintaining low steady-state levels of superoxide under conditions of mitochondrial dysfunction. This mitochondrial activity of ARF is independent of its known autophagic and p53-dependent functions, and involves the evolutionarily conserved acidic motif GHDDGQ, which exhibits weak homology to BCL-2 homology 3 (BH3) domains and mediates interaction with BCL-xL--an important regulator of mitochondrial redox homeostasis. Melanoma-predisposing CDKN2A germline mutations, which affect conserved glycine and aspartate residues within the GHDDGQ motif, impair the ability of ARF to control superoxide production and suppress growth of melanoma cells in vivo. These results reveal an important cell-protective function of ARF that links mitochondrial dysfunction and susceptibility to melanoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Cell Respiration
  • Cells, Cultured
  • Genetic Predisposition to Disease
  • Humans
  • Melanocytes / metabolism*
  • Melanoma / genetics*
  • Mitochondrial Diseases / metabolism*
  • Superoxides / metabolism*
  • Tumor Suppressor Protein p14ARF / metabolism*
  • bcl-X Protein / metabolism

Substances

  • BCL2L1 protein, human
  • Tumor Suppressor Protein p14ARF
  • bcl-X Protein
  • Superoxides