Forced expression of survivin-2B abrogates mitotic cells and induces mitochondria-dependent apoptosis by blockade of tubulin polymerization and modulation of Bcl-2, Bax, and survivin

Xiang Ling, Qiuying Cheng, Jennifer D. Black, Fengzhi Li

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39 Citations (Scopus)

Abstract

It has been previously shown that both survivin and the survivin splice variant survivin-2B are localized in mitochondria. Whereas the mechanism involved in blockade of mitochondria-mediated apoptosis by survivin has been extensively studied, the role of survivin-2B in regulation of apoptosis has not been well defined. In the present study, we report that in addition to mitochondria, survivin-2B is also localized in the microtubule organization center (MTOC) and, in contrast to other survivin isoforms (i.e. survivin and survivin-ΔEx3), behaves as a proapoptotic molecule. We show that forced expression of survivin-2B blocks tubulin polymerization, ablates mitotic cells, and induces mitochondria-dependent apoptosis. The mitochondria-mediated apoptosis induced by survivin-2B was indicated by Smac release from mitochondria, activation of caspases 9 and 3, and loss of mitochondrial potential, while caspase-8 remained inactive. Further analysis of the mechanism for the mitochondria-associated events of apoptosis induced by forced expression of survivin-2B revealed down-regulation of the pro-survival factor Bcl-2 and up-regulation of the pro-apoptotic factor Bax in mitochondria, while the apoptosis-inducing factor (AIF) remains unchanged. Our studies further showed that taxol (paclitaxel) treatment of cancer cells not only up-regulates survivin but also down-regulates survivin-2B and that forced expression of survivin-2B sensitizes cells to taxol-induced cell growth inhibition and cell death, while silencing of endogenous survivin-2B transcripts by survivin-2B-specific siRNA made cells resistant to taxol treatment. These findings advance our current knowledge about survivin-2B and may help to develop novel approaches for cancer treatment.

Original languageEnglish (US)
Pages (from-to)27204-27214
Number of pages11
JournalJournal of Biological Chemistry
Volume282
Issue number37
DOIs
StatePublished - Sep 14 2007

Fingerprint

Mitochondria
Tubulin
Polymerization
Modulation
Apoptosis
Paclitaxel
Up-Regulation
Down-Regulation
Apoptosis Inducing Factor
Oncology
Caspase 9
Caspase 8
Cell growth
Cell death
Microtubules
Caspase 3
Small Interfering RNA
Neoplasms
Protein Isoforms
Cell Death

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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title = "Forced expression of survivin-2B abrogates mitotic cells and induces mitochondria-dependent apoptosis by blockade of tubulin polymerization and modulation of Bcl-2, Bax, and survivin",
abstract = "It has been previously shown that both survivin and the survivin splice variant survivin-2B are localized in mitochondria. Whereas the mechanism involved in blockade of mitochondria-mediated apoptosis by survivin has been extensively studied, the role of survivin-2B in regulation of apoptosis has not been well defined. In the present study, we report that in addition to mitochondria, survivin-2B is also localized in the microtubule organization center (MTOC) and, in contrast to other survivin isoforms (i.e. survivin and survivin-ΔEx3), behaves as a proapoptotic molecule. We show that forced expression of survivin-2B blocks tubulin polymerization, ablates mitotic cells, and induces mitochondria-dependent apoptosis. The mitochondria-mediated apoptosis induced by survivin-2B was indicated by Smac release from mitochondria, activation of caspases 9 and 3, and loss of mitochondrial potential, while caspase-8 remained inactive. Further analysis of the mechanism for the mitochondria-associated events of apoptosis induced by forced expression of survivin-2B revealed down-regulation of the pro-survival factor Bcl-2 and up-regulation of the pro-apoptotic factor Bax in mitochondria, while the apoptosis-inducing factor (AIF) remains unchanged. Our studies further showed that taxol (paclitaxel) treatment of cancer cells not only up-regulates survivin but also down-regulates survivin-2B and that forced expression of survivin-2B sensitizes cells to taxol-induced cell growth inhibition and cell death, while silencing of endogenous survivin-2B transcripts by survivin-2B-specific siRNA made cells resistant to taxol treatment. These findings advance our current knowledge about survivin-2B and may help to develop novel approaches for cancer treatment.",
author = "Xiang Ling and Qiuying Cheng and Black, {Jennifer D.} and Fengzhi Li",
year = "2007",
month = "9",
day = "14",
doi = "10.1074/jbc.M705161200",
language = "English (US)",
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journal = "Journal of Biological Chemistry",
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T1 - Forced expression of survivin-2B abrogates mitotic cells and induces mitochondria-dependent apoptosis by blockade of tubulin polymerization and modulation of Bcl-2, Bax, and survivin

AU - Ling, Xiang

AU - Cheng, Qiuying

AU - Black, Jennifer D.

AU - Li, Fengzhi

PY - 2007/9/14

Y1 - 2007/9/14

N2 - It has been previously shown that both survivin and the survivin splice variant survivin-2B are localized in mitochondria. Whereas the mechanism involved in blockade of mitochondria-mediated apoptosis by survivin has been extensively studied, the role of survivin-2B in regulation of apoptosis has not been well defined. In the present study, we report that in addition to mitochondria, survivin-2B is also localized in the microtubule organization center (MTOC) and, in contrast to other survivin isoforms (i.e. survivin and survivin-ΔEx3), behaves as a proapoptotic molecule. We show that forced expression of survivin-2B blocks tubulin polymerization, ablates mitotic cells, and induces mitochondria-dependent apoptosis. The mitochondria-mediated apoptosis induced by survivin-2B was indicated by Smac release from mitochondria, activation of caspases 9 and 3, and loss of mitochondrial potential, while caspase-8 remained inactive. Further analysis of the mechanism for the mitochondria-associated events of apoptosis induced by forced expression of survivin-2B revealed down-regulation of the pro-survival factor Bcl-2 and up-regulation of the pro-apoptotic factor Bax in mitochondria, while the apoptosis-inducing factor (AIF) remains unchanged. Our studies further showed that taxol (paclitaxel) treatment of cancer cells not only up-regulates survivin but also down-regulates survivin-2B and that forced expression of survivin-2B sensitizes cells to taxol-induced cell growth inhibition and cell death, while silencing of endogenous survivin-2B transcripts by survivin-2B-specific siRNA made cells resistant to taxol treatment. These findings advance our current knowledge about survivin-2B and may help to develop novel approaches for cancer treatment.

AB - It has been previously shown that both survivin and the survivin splice variant survivin-2B are localized in mitochondria. Whereas the mechanism involved in blockade of mitochondria-mediated apoptosis by survivin has been extensively studied, the role of survivin-2B in regulation of apoptosis has not been well defined. In the present study, we report that in addition to mitochondria, survivin-2B is also localized in the microtubule organization center (MTOC) and, in contrast to other survivin isoforms (i.e. survivin and survivin-ΔEx3), behaves as a proapoptotic molecule. We show that forced expression of survivin-2B blocks tubulin polymerization, ablates mitotic cells, and induces mitochondria-dependent apoptosis. The mitochondria-mediated apoptosis induced by survivin-2B was indicated by Smac release from mitochondria, activation of caspases 9 and 3, and loss of mitochondrial potential, while caspase-8 remained inactive. Further analysis of the mechanism for the mitochondria-associated events of apoptosis induced by forced expression of survivin-2B revealed down-regulation of the pro-survival factor Bcl-2 and up-regulation of the pro-apoptotic factor Bax in mitochondria, while the apoptosis-inducing factor (AIF) remains unchanged. Our studies further showed that taxol (paclitaxel) treatment of cancer cells not only up-regulates survivin but also down-regulates survivin-2B and that forced expression of survivin-2B sensitizes cells to taxol-induced cell growth inhibition and cell death, while silencing of endogenous survivin-2B transcripts by survivin-2B-specific siRNA made cells resistant to taxol treatment. These findings advance our current knowledge about survivin-2B and may help to develop novel approaches for cancer treatment.

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