Mitochondrial p32 is a critical mediator of ARF-induced apoptosis

Cancer Cell. 2008 Jun;13(6):542-53. doi: 10.1016/j.ccr.2008.04.002.

Abstract

The shared exon 2 of the p14ARF-p16INK4a locus is frequently mutated in human cancers. However, in contrast to the exon 1beta-encoded N-terminal half of ARF, the function of the exon 2-encoded C-terminal half of ARF has been elusive. Here, we report that the mitochondrial protein p32/C1QBP binds the ARF C terminus. We show that p32 is required for ARF to localize to mitochondria and induce apoptosis, and that ARF mutations specifically disrupting p32 binding can impair both of these functions. Wild-type ARF, but not a p32-binding-deficient ARF mutant, localizes to mitochondria, reduces mitochondrial membrane potential, and sensitizes cells to p53-induced apoptosis. These findings provide a potential explanation for the frequent human cancer mutations targeting the ARF C terminus.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Exons
  • Humans
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / metabolism*
  • Membrane Potential, Mitochondrial
  • Mice
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Mutation
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein Transport
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Transfection
  • Tumor Suppressor Protein p14ARF / genetics
  • Tumor Suppressor Protein p14ARF / metabolism*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • C1QBP protein, human
  • C1qbp protein, mouse
  • Carrier Proteins
  • Hyaluronan Receptors
  • Mitochondrial Proteins
  • RNA, Small Interfering
  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Protein p53
  • mitochondrial p32 protein, human