Survivin splice variants regulate the balance between proliferation and cell death.
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-DeltaEx3 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.
Caldas
Hugo
H
Center for Childhood Cancer, Columbus Children's Research Institute, The Ohio State University, Columbus, OH, USA.
Jiang
Yuying
Y
Holloway
Michael P
MP
Fangusaro
Jason
J
Mahotka
Csaba
C
Conway
Edward M
EM
Altura
Rachel A
RA
D017398:Alternative Splicing; D017209:Apoptosis / Q000235:genetics; D001932:Brain Neoplasms; D016923:Cell Death / Q000235:genetics*; D002455:Cell Division / Q000235:genetics*; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms; D014644:Genetic Variation; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008527:Medulloblastoma; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins; D016133:Polymerase Chain Reaction; D000077022:Survivin; D014162:Transfection
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin