Regulation of apoptosis at cell division by p34cdc2 phosphorylation of survivin

Regulation of apoptosis at cell division by p34^cdc2 phosphorylation of survivin

Departments of ^†Pathology, ^‡Dermatology, and ^§Genetics, Boyer Center for Molecular Medicine, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536; ^¶MIA, Universita' Milano-Bicocca, Via Donizetti 106, Monza 20052, Italy; and ^‖DIBIT San Raffaele Scientific Institute, Via Olgettina 58, Milano 20132, Italy

Edited by Bert Vogelstein, Johns Hopkins Oncology Center, Baltimore, MD, and approved September 21, 2000 (received for review August 15, 2000)

Abstract

The interface between apoptosis (programmed cell death) and the cell cycle is essential to preserve homeostasis and genomic integrity. Here, we show that survivin, an inhibitor of apoptosis over-expressed in cancer, physically associates with the cyclin-dependent kinase p34^cdc2 on the mitotic apparatus, and is phosphorylated on Thr³⁴ by p34^cdc2-cyclin B1, in vitro and in vivo. Loss of phosphorylation on Thr³⁴ resulted in dissociation of a survivin-caspase-9 complex on the mitotic apparatus, and caspase-9-dependent apoptosis of cells traversing mitosis. These data identify survivin as a mitotic substrate of p34^cdc2-cyclin B1 and suggest that survivin phosphorylation on Thr³⁴ may be required to preserve cell viability at cell division. Manipulation of this pathway may facilitate the elimination of cancer cells at mitosis.

Footnotes

↵ ** To whom reprint requests should be addressed. E-mail address: dario.altieri{at}yale.edu.
This paper was submitted directly (Track II) to the PNAS office.
Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.240390697.
Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.240390697
Abbreviations:

IAP,

inhibitor of apoptosis;

BIR,

baculovirus IAP repeat;

HA,

hemagglutinin epitope;

GST,

glutathione S-transferase;

GFP,

green fluorescent protein;

DAPI,

4′,6-diamidino-2-phenylindole;

Tet,

tetracycline