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The autophagic inducer smARF interacts with and is stabilized by the mitochondrial p32 protein


The alternative reading frame (ARF) mRNA encodes two pro-death proteins, the nucleolar p19ARF and a shorter mitochondrial isoform, named smARF (hsmARF in human). While p19ARF can inhibit cell growth by causing cell cycle arrest or type I apoptotic cell death, smARF is able to induce type II autophagic cell death. Inappropriate proliferative signals generated by proto-oncogenes, such as c-Myc and E2F1, can elevate both p19ARF and smARF proteins. Here, we reveal a novel means of regulation of smARF protein steady state levels through its interactions with the mitochondrial p32. The p32 protein physically interacts with both human and murine smARF, and colocalizes with these short isoforms to the mitochondria. Remarkably, knocking down p32 protein levels significantly reduced the steady state levels of smARF by increasing its turn over. As a consequence, the ability of ectopically expressed smARF to induce autophagy and to cause mitochondrial membrane dissipation was significantly reduced. In contrast, the protein levels of full-length p19ARF, which mainly resides in the nucleolus, were not influenced by p32 depletion, suggesting that p32 exclusively stabilizes the mitochondrial smARF protein. Thus the interaction with p32 provides a means of specifically regulating the expression of the recently identified autophagic inducer, smARF, and adds yet another layer of complexity to the multifaceted regulation of the ARF gene.

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We thank WC Russell for providing the polyclonal antibody against p32. We thank S Bialik for critical reading of the article, E Zalckvar and G Tarcic for help and advice. This work was supported by grants from the European Union (LSHB-CT-2004-511983) (to AK) and by the Center of Excellence grant from the Flight Attendant Medical Research Institute (FAMRI) to AK and MO. AK is the incumbent of Helena Rubinstein Chair of Cancer Research.

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Correspondence to A Kimchi.

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Reef, S., Shifman, O., Oren, M. et al. The autophagic inducer smARF interacts with and is stabilized by the mitochondrial p32 protein. Oncogene 26, 6677–6683 (2007).

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