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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 Article has an altmetric score of 4

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 9

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Mitochondrial survivin promotes tumorigenicity. (A) Colony formation in ...
Mitochondrial survivin promotes tumorigenicity. (A) Colony formation in soft agar. Differentially transfected INS-1 cells were plated in semisolid medium and scored for colony formation by phase-contrast microscopy. (B) Quantification of colony formation in soft agar. The experimental conditions were as in A. Data are the mean ± SD of a representative experiment of at least 2 independent determinations. ***P = 0.0001. (C) Kinetics of tumor growth. Stably transfected INS-1 cells were injected subcutaneously in the flank of CB17 SCID/beige mice, and tumor volume was determined at the indicated time intervals. Statistical analysis compared growth of INS-1/Surv versus INS-1/MT-S tumors at day 28 (P = 0.024), day 35 (P = 0.0069), and day 45 (P = 0.015). *P < 0.05; **P < 0.01. (D) Histology. Tissue sections from the indicated INS-1 tumors were stained by H&E, Ki67 reactivity as a measure of cell proliferation, and TUNEL as a measure of apoptosis, in vivo. Magnification, ×400. (E) Mitotic index in vivo. The number of Ki67-positive (proliferating) cells was counted in 7 independent fields, each containing an average of 400 cells. #P = 0.031. (F) Apoptotic index in vivo. The number of TUNEL-positive (apoptotic) cells was counted in 7 independent fields, each containing an average of 400 cells.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 5 patents
Mentioned by 1 peer review sites
10 readers on Mendeley
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