ARF induces autophagy by virtue of interaction with Bcl-xl

J Biol Chem. 2009 Jan 30;284(5):2803-2810. doi: 10.1074/jbc.M804705200. Epub 2008 Dec 2.


The ARF tumor suppressor controls a well-described p53/Mdm2-dependent oncogenic stress checkpoint. In addition, ARF has recently been shown to localize to mitochondria, and to induce autophagy; however, this has never before been demonstrated for endogenous ARF, and the molecular basis for this activity of ARF has not been elucidated. Using an unbiased mass spectrometry-based approach, we show that mitochondrial ARF interacts with the Bcl2 family member Bcl-xl, which normally protects cells from autophagy by inhibiting the Beclin-1/Vps34 complex, which is essential for autophagy. We find that increased expression of ARF decreases Beclin-1/Bcl-xl complexes in cells, thereby providing a basis for ARF-induced autophagy. Our data also indicate that silencing p53 leads to high levels of ARF and increased autophagy, thereby providing a possible basis for the finding by others that p53 inhibits autophagy. The combined data support the premise that ARF induces autophagy in a p53-independent manner in part by virtue of its interaction with Bcl-xl.

Publication types

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

MeSH terms

  • Autophagy / physiology*
  • Blotting, Western
  • Cell Line, Tumor
  • Humans
  • Immunoprecipitation
  • Tumor Suppressor Protein p14ARF / metabolism
  • Tumor Suppressor Protein p14ARF / physiology*
  • bcl-X Protein / metabolism*


  • Tumor Suppressor Protein p14ARF
  • bcl-X Protein