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 o...

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Veröffentlicht in:Cell cycle (Georgetown, Tex.) Tex.), 2010-02, Vol.9 (4), p.829-839
Hauptverfasser: Irvine, Mal, Philipsz, Suzanah, Frausto, Monika, Mijatov, Branka, Gallagher, Stuart J, Fung, Carina, Becker, Therese M, Kefford, Richard F, Rizos, Helen
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container_issue 4
container_start_page 829
container_title Cell cycle (Georgetown, Tex.)
container_volume 9
creator Irvine, Mal
Philipsz, Suzanah
Frausto, Monika
Mijatov, Branka
Gallagher, Stuart J
Fung, Carina
Becker, Therese M
Kefford, Richard F
Rizos, Helen
description 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.
doi_str_mv 10.4161/cc.9.4.10785
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source MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central
subjects Amino Acid Sequence
Animals
Apoptosis
bcl-X Protein - metabolism
Cell Line, Tumor
Humans
Hydrophobic and Hydrophilic Interactions
Mice
Mitochondria - metabolism
Mitochondrial Proteins - metabolism
Molecular Sequence Data
Protein Structure, Tertiary
Sequence Alignment
Signal Transduction
Tumor Suppressor Protein p14ARF - metabolism
Tumor Suppressor Protein p53 - metabolism
title Amino terminal hydrophobic import signals target the p14(ARF) tumor suppressor to the mitochondria
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