Mitochondrial survivin inhibits apoptosis and promotes tumorigenesis.
Evasion of apoptosis is a hallmark of cancer, but the molecular circuitries of this process are not understood. Here we show that survivin, a member of the inhibitor of apoptosis gene family that is overexpressed in cancer, exists in a novel mitochondrial pool in tumor cells. In response to cell death stimulation, mitochondrial survivin is rapidly discharged in the cytosol, where it prevents caspase activation and inhibits apoptosis. Selective targeting of survivin to mitochondria enhances colony formation in soft agar, accelerates tumor growth in immunocompromised animals, and abolishes tumor cell apoptosis in vivo. Therefore, mitochondrial survivin orchestrates a novel pathway of apoptosis inhibition, which contributes to tumor progression.
Department of Cancer Biology and the Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Takehiko
T
Dohi
Elena
E
Beltrami
Nathan R
NR
Wall
Janet
J
Plescia
Dario C
DC
Altieri
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D019286:Endopeptidase K / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D020287:In Situ Nick-End Labeling; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009363:Neoplasm Proteins; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D013347:Subcellular Fractions / Q000378:metabolism; D000077022:Survivin
C107489:BIRC5 protein, human; D004791:Enzyme Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D000077022:Survivin; D019286:Endopeptidase K; D020169:Caspases; D019311:Staurosporine