Survivin splice variants regulate the balance between proliferation and cell death

Hugo Caldas, Yuying Jiang, Michael P. Holloway, Jason Fangusaro, Csaba Mahotka, Edward M. Conway, Rachel A. Altura*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

169 Scopus citations

Abstract

Survivin is an inhibitor of apoptosis protein that also plays critical roles in regulating the cell cycle and mitosis. Its prominent expression in essentially all human malignancies, and low or absent expression in most normal tissues, suggests that it would be an ideal target for cancer-directed therapy. Impeding development of safe and effective survivin antagonists for clinical use is a lack of understanding of the molecular mechanisms by which survivin differentially affects apoptosis and cell division, in normal and malignant cells. We show that the diverse functional roles of survivin can be explained, in part, by its heterodimerization with survivin splice variants in tumor cells. Survivin and survivin-ΔEx3 interact within the mitochondria where they may inhibit mitochondrial-dependent apoptosis. If the expression of all survivin forms is eliminated by siRNA transfections, cells undergo both apoptosis and defective cell division. Overall, we provide new insights suggesting that targeting specific survivin isoforms, rather than survivin alone, may selectively and effectively destroy tumor cells. These findings are likely to have a significant impact in the design of biologic agents for clinical therapy.

Original languageEnglish (US)
Pages (from-to)1994-2007
Number of pages14
JournalOncogene
Volume24
Issue number12
DOIs
StatePublished - Mar 17 2005

Keywords

  • Apoptosis
  • Cell division
  • Drug therapy
  • Mitosis
  • Neoplasms

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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