The ARF tumor suppressor can promote the progression of some tumors.
p14/p19ARF (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.
Humbey
Olivier
O
Division of Medical Sciences, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Pimkina
Julia
J
Zilfou
Jack T
JT
Jarnik
Michal
M
Dominguez-Brauer
Carmen
C
Burgess
Darren J
DJ
Eischen
Christine M
CM
Murphy
Maureen E
ME
D000818:Animals; D001343:Autophagy / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis / Q000235:genetics*; D018450:Disease Progression; D005347:Fibroblasts; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53