Mitochondrial p32 is a critical mediator of ARF-induced apoptosis.
The shared exon 2 of the p14ARF-p16INK4a locus is frequently mutated in human cancers. However, in contrast to the exon 1beta-encoded N-terminal half of ARF, the function of the exon 2-encoded C-terminal half of ARF has been elusive. Here, we report that the mitochondrial protein p32/C1QBP binds the ARF C terminus. We show that p32 is required for ARF to localize to mitochondria and induce apoptosis, and that ARF mutations specifically disrupting p32 binding can impair both of these functions. Wild-type ARF, but not a p32-binding-deficient ARF mutant, localizes to mitochondria, reduces mitochondrial membrane potential, and sensitizes cells to p53-induced apoptosis. These findings provide a potential explanation for the frequent human cancer mutations targeting the ARF C terminus.
Itahana
Koji
K
Department of Radiation Oncology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7512, USA.
Zhang
Yanping
Y
D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005091:Exons; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
C087299:C1QBP protein, human; C490193:C1qbp protein, mouse; D002352:Carrier Proteins; D018960:Hyaluronan Receptors; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53