Multisite mutation of monomer survivin with enhanced effect on apoptosis regulation of breast cancer cells

Guoying Dai, Wenyun Zheng, Xingyuan Ma, Ping Wang

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Survivin is an important protein in regulating both cell apoptosis and proliferation. It has attracted growing attentions in recent years as a promising target for cancer therapy. Previous studies have revealed that monomeric survivin regulated apoptosis in a more significant way than the wild-type survivin that generally contains a large portion of its dimers. In order to investigate the roles of monomeric mutant survivin apoptosis and cell cycle regulation of human cancer cells, we developed and tested three dominant-negative mutants with multisite mutations (MSM) including TAT-survivin34/101/102, TAT-survivin34/117/101/102 and TAT-survivin117/101/102. Results revealed that MSM mutants remained as monomers under ambient conditions, and induced cells (breast cancer Bcap-37 cells) apoptosis even more efficiently, primarily through the caspase-dependent and Bcl-2-related pathways, than non-monomeric mutants. We further identified that the TAT-survivin34/101/102 and TAT-survivin117/101/102 MSM significantly inhibited the proliferation of Bcap-37 cells and arrested cells in S and G2/M phases, while TAT-survivin34/117/101/102 arrested cells in G2/M phase. It appeared to us that TAT-survivin34/101/102 and TAT-survivin117/101/102 also inhibited cell proliferation more significantly. These findings suggest that such MSM afford monomeric survivin with promising potentials for cancer therapy.

Original languageEnglish (US)
Pages (from-to)111-118
Number of pages8
JournalBiomedicine and Pharmacotherapy
Volume69
DOIs
StatePublished - Feb 1 2015

Bibliographical note

Funding Information:
We thank Yanyan Kang for valuable discussion on SEC analysis of survivin mutants. This study was supported by the National Natural Science Foundation ( 30873190; 31471659; 21303050 ), Science and technology innovation action plan of Shanghai ( 14431904300 ) and the National Science Research Project “Significant New Drugs Created” of Eleventh Five-year Plan ( 2009ZX09103-693 ). Dai thanks Chinese Scholarship Council for the support of an international scholarship for visiting research at UMN. Wang thanks sabbatical support from UMN.

Publisher Copyright:
© 2014 Elsevier Masson SAS.

Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.

Keywords

  • Apoptosis
  • Breast cancer
  • Cell cycle regulation
  • Protein engineering
  • Site-specific mutagenesis
  • Survivin

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