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Pimkina J , Humbey O , Zilfou JT , Jarnik M , Murphy ME
ARF Induces Autophagy by Virtue of Interaction with Bcl-xl
Journal of Biological Chemistry. 2009 Jan;284(5) :2803-2810
PMCID: PMC2631963   
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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.
ISI Document Delivery No.: 397ZL Pimkina, Julia Humbey, Olivier Zilfou, Jack T. Jarnik, Michal Murphy, Maureen E. AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC