Amino terminal hydrophobic import signals target the p14(ARF) tumor suppressor to the mitochondria.
The p14(ARF) tumor suppressor is frequently targeted for inactivation in many human cancers and in individuals predisposed to cutaneous melanoma. The functions of p14(ARF) are closely linked with its subcellular distribution. Nucleolar p14(ARF) dampens ribosome biosynthesis and nucleoplasmic forms of p14(ARF) activate the p53 pathway and induce cell cycle arrest. p14(ARF) can also be recruited to mitochondria where it interacts with many mitochondrial proteins, including Bcl-x(L) and p32 to induce cell death. It has been suggested that the movement of p14(ARF) to mitochondria requires its interaction with p32, but we now show that the ARF-p32 interaction is not necessary for the accumulation of p14(ARF) in mitochondria. Instead, highly hydrophobic domains within the amino-terminal half of p14(ARF) act as mitochondrial import sequences. We suggest that once this hydrophobic pocket is exposed, possibly in a stimulus-dependent manner, it accelerates the mitochondrial import of p14(ARF). This allows the interaction of p14(ARF) with mitochondrial proteins, including p32 and enables p53-independent cell death.
Irvine
Mal
M
Westmead Institute for Cancer Research and Melanoma Institute of Australia, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, NSW, Australia.
Philipsz
Suzanah
S
Frausto
Monika
M
Mijatov
Branka
B
Gallagher
Stuart J
SJ
Fung
Carina
C
Becker
Therese M
TM
Kefford
Richard F
RF
Rizos
Helen
H
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins; D045744:Cell Line, Tumor; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D015398:Signal Transduction; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
C087299:C1QBP protein, human; D002352:Carrier Proteins; D024101:Mitochondrial Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein