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The ARF Tumor Suppressor Can Promote the Progression of Some Tumors

Divisions of ¹ Medical Sciences and ² Basic Sciences, Fox Chase Cancer Center, Philadelphia, Pennsylvania; ³ Zilfou Therapeutics, Inc., Allentown, Pennsylvania; ⁴ University of Illinois at Chicago, Chicago, Illinois; ⁵ Cold Spring Harbor Laboratory, Cold Spring Harbor, New York; and ⁶ Vanderbilt University School of Medicine, Nashville, Tennessee

Requests for reprints: Maureen E. Murphy, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111. Phone: 215-728-5684; Fax: 215-728-4333; E-mail: Maureen.Murphy{at}FCCC.edu.

Key Words: ARF • mitochondria • autophagy

p14/p19^ARF (ARF) is a tumor suppressor gene that is frequently mutated in human cancer. ARF has multiple tumor suppressor functions, some of which are mediated by signaling to p53. Surprisingly, a significant fraction of human tumors retain persistently high levels of ARF, suggesting that ARF may possess a prosurvival function. We show that ARF protein is markedly up-regulated in cells exposed to nutrient starvation. Cells with silenced ARF show reduced autophagy and reduced viability when placed under conditions of starvation. We show for the first time that ARF silencing can limit the progression of some tumors, such as lymphoma, but not others, such as E1A/Ras-induced tumors. Specifically, myc-driven lymphomas with mutant p53 tend to overexpress ARF; we show that silencing ARF in these tumors greatly impedes their progression. These data are the first to show that ARF can act in a p53-independent manner to promote the progression of some tumors. [Cancer Res 2008;68(23):9608–13]

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