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Author

Kang, Byoung Heon
Cancer Biology Lab
Research Interests
  • Mitochondrial chaperones, cancer biology, cell death, metabolism, cancer stem cells, cancer therapeutics development

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Developmental Control of Apoptosis by the Immunophilin Aryl Hydrocarbon Receptor-interacting Protein (AIP) Involves Mitochondrial Import of the Survivin Protein

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Title
Developmental Control of Apoptosis by the Immunophilin Aryl Hydrocarbon Receptor-interacting Protein (AIP) Involves Mitochondrial Import of the Survivin Protein
Author
Kang, Byoung HeonXia, FangPop, RamonaDohi, TakehikoSocolovsky, MeravAltieri, Dario C.
Keywords
Apoptosis; Aryl hydrocarbons; Cell divisions; Cell survival; Cytoprotective properties; Cytosolic; Cytosolic factors; Embryonic lethality; Heat shock protein; Immunophilins; In-vivo; Mitochondrial import; Multifunctional protein; Receptor-interacting proteins; Recombinant protein; Survivin; Transmembrane potentials; Tumor cells
Issue Date
201105
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Citation
JOURNAL OF BIOLOGICAL CHEMISTRY, v.286, no.19, pp.16758 - 16767
Abstract
Survivin is a multifunctional protein with essential roles in cell division and inhibition of apoptosis, but the molecular underpinnings of its cytoprotective properties are poorly understood. Here we show that homozygous deletion of the aryl hydrocarbon receptor-interacting protein (AIP), a survivin-associated immunophilin, causes embryonic lethality in mice by embryonic day 13.5-14, increased apoptosis of Ter119(-)/CD71(-) early erythropoietic progenitors, and loss of survivin expression in its cytosolic and mitochondrial compartments in vivo. In import assays using recombinant proteins, AIP directly mediated the import of survivin to mitochondria, thus enabling its anti-apoptotic function, whereas a survivin 1-141 mutant that does not bind AIP was not imported to mitochondria and failed to inhibit apoptosis. AIP-directed mitochondrial import of survivin did not affect cell division, was independent of the organelle transmembrane potential, did not require the chaperone Heat Shock Protein 90 (Hsp90), and was inhibited by cytosolic factor(s) present in normal cells. shRNA knockdown of the mitochondrial import receptor Tom20 abolished mitochondrial import of survivin and sensitized tumor cells to apoptosis, whereas silencing of Tom70 had no effect. Therefore, an AIP-Tom20 recognition contributes to cell survival in development and cancer by mediating the mitochondrial import of survivin.
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DOI
http://dx.doi.org/10.1074/jbc.M110.210120
ISSN
0021-9258
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