The Journal of Experimental Medicine
Keystone Symposia
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Published 17 May 2004. doi:10.1084/jem.20032033
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 10, 1343-1354
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Inflammation-associated Cell Cycle–independent Block of Apoptosis by Survivin in Terminally Differentiated Neutrophils

Frank Altznauer1, Sibylla Martinelli1, Shida Yousefi1, Christine Thürig3, Inès Schmid1, Edward M. Conway5, Martin H. Schöni4, Peter Vogt6, Christoph Mueller2, Martin F. Fey3, Uwe Zangemeister-Wittke7, and Hans-Uwe Simon1

1 Department of Pharmacology, 2 Department of Pathology, 3 Institute of Medical Oncology and 4 Department of Pediatrics, Inselspital, University of Bern, CH-3010 Bern, Switzerland
5 Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, University of Leuven, B-3000 Leuven, Belgium
6 Institute of Clinical Pathology, University Hospital Zurich, CH-8091 Zurich, Switzerland
7 Department of Oncology, University Hospital Zurich, CH-8044 Zurich, Switzerland

Address correspondence to Hans-Uwe Simon, Dept. of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland. Phone: 41-31-632-3281; Fax: 41-31-632-4992; email: hus{at}pki.unibe.ch

Survivin has received great attention due to its expression in many human tumors and its potential as a therapeutic target in cancer. Survivin expression has been described to be cell cycle–dependent and restricted to the G2-M checkpoint, where it inhibits apoptosis in proliferating cells. In agreement with this current view, we found that survivin expression was high in immature neutrophils, which proliferate during differentiation. In contrast with immature cells, mature neutrophils contained only little or no survivin protein. Strikingly, these cells reexpressed survivin upon granulocyte/macrophage colony-stimulating factor (CSF) or granulocyte CSF stimulation in vitro and under inflammatory conditions in vivo. Moreover, survivin-deficient mature neutrophils were unable to increase their lifespan after survival factor exposure. Together, our findings demonstrate the following: (a) overexpression of survivin occurs in primary, even terminally differentiated cells and is not restricted to proliferating cells; and (b) survivin acts as an inhibitor of apoptosis protein in a cell cycle–independent manner. Therefore, survivin plays distinct and independent roles in the maintenance of the G2-M checkpoint and in apoptosis control, and its overexpression is not restricted to proliferating cells. These data provide new insights into the regulation and function of survivin and have important implications for the pathogenesis, diagnosis, and treatment of inflammatory diseases and cancer.

Key Words: antisense • cancer • cytokines • differentiation • infection

F. Altznauer and S. Martinelli contributed equally to this work.

Abbreviations used in this paper: CF, cystic fibrosis; GAPDH, glyceraldehyde-3–phosphate dehydrogenase; IAP, inhibitor of apoptosis protein; MPO, myeloperoxidase; Smac, second mitochondrial activator of caspase.


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