ARF induces autophagy by virtue of interaction with Bcl-xl.
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.
Pimkina
Julia
J
Division of Medical Sciences, Philadelphia, Pennsylvania 19111; Smolensk State Medical Academy Graduate Program, Philadelphia, Pennsylvania 19111.
Humbey
Olivier
O
Division of Medical Sciences, Philadelphia, Pennsylvania 19111.
Zilfou
Jack T
JT
Zilfou Therapeutics, Inc., Allentown, Pennsylvania 18104.
Jarnik
Michal
M
Division of Basic Sciences, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111.
Murphy
Maureen E
ME
Division of Medical Sciences, Philadelphia, Pennsylvania 19111. Electronic address: Maureen.Murphy@FCCC.edu.
D001343:Autophagy / Q000502:physiology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D006801:Humans; D047468:Immunoprecipitation; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism / Q000502:physiology*; D051020:bcl-X Protein / Q000378:metabolism*
D025803:Tumor Suppressor Protein p14ARF; D051020:bcl-X Protein