The ARF tumor suppressor is best known for its ability to stabilize p53, mediated by inhibition of the p53 ubiquitin ligase MDM2. Additionally, ARF has multiple tumor suppressor functions that are independent of p53: these involve interaction with a number of proteins with roles in cell proliferation, including nucleophosmin, NIAM, c-myc, E2F-1, DP1, and others (see 1
for review). Despite its multiple growth suppression functions, ARF is inexplicably overexpressed in a significant fraction of human tumors, including up to 50% of Burkitt’s lymphomas (2, 3
), as well as the majority of tumors with mutant p53 (4
). To date, the overwhelming majority of studies on ARF have focused on its tumor suppressor roles, and no groups have addressed the possibility that ARF might promote the survival of a subset of tumors.
A role for ARF in autophagy has recently been discovered. Specifically, a small molecular weight variant of this protein generated by translation from an internal methionine has been shown to localize to mitochondria and induce autophagy (5, 6
). More recently, another group has shown that full-length ARF can likewise induce autophagy (7
). Autophagy is a process of lysosome-mediated self-digestion that occurs during periods of nutrient deprivation (see 8
for review). This process is necessary for cell survival; following nutrient starvation proteins and organelles are degraded, and the released amino acids are utilized for the synthesis of essential proteins. Whereas recent studies have shown that ARF can induce autophagy, the relevance of ARF to starvation-induced autophagy, and the significance of this finding to cancer development, have not been addressed. In this study we show that nutrient deprivation leads to significant increases in ARF protein. We show that ARF-mediated autophagy can protect cells from periods of nutrient deprivation. Further, we show that lymphomas with ARF silenced demonstrate impaired progression in immunocompromised mice. Our data support the premise that ARF can enhance tumor development under certain circumstances, and that some tumors with mutant p53 may retain ARF in order to promote survival under metabolic stress.