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Mitochondrial survivin inhibits apoptosis and promotes tumorigenesis
Takehiko Dohi, … , Janet Plescia, Dario C. Altieri
Takehiko Dohi, … , Janet Plescia, Dario C. Altieri
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1117-1127. https://doi.org/10.1172/JCI22222.
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Article Oncology

Mitochondrial survivin inhibits apoptosis and promotes tumorigenesis

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Abstract

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.

Authors

Takehiko Dohi, Elena Beltrami, Nathan R. Wall, Janet Plescia, Dario C. Altieri

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Figure 7

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Mitochondrial release of survivin during apoptosis. (A) Effect on cytoch...
Mitochondrial release of survivin during apoptosis. (A) Effect on cytochrome c release. INS-1 cells stably transfected with MT-GFP or MT-S were treated with staurosporine, harvested at the indicated time intervals, and analyzed by immunoblotting. (B) Fluorescence microscopy. INS-1/MT-S cells were treated with staurosporine and analyzed for cytosolic redistribution of GFP. (C) Single-cell analysis. Areas corresponding to mitochondria (yellow squares) or cytosol (gray circles) were quantitatively analyzed for changes in fluorescence distribution before (None) or after staurosporine treatment (left panel). Right panel: Quantification of single-cell analysis. Changes in fluorescence intensity in individual mitochondrial or cytosolic areas were analyzed in the presence or absence of staurosporine treatment. Data represent an average of 16 individual determinations for mitochondrial areas and 14 individual determinations for cytosolic areas. (D) Time course of mitochondrial release of survivin during cell death. INS-1/MT-S cells were treated with staurosporine, and isolated mitochondrial or cytosolic fractions were analyzed at the indicated time intervals by immunoblotting. Right panel: Densitometric quantification of time-dependent depletion of mitochondrial survivin in response to staurosporine.

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