Inflammation-associated cell cycle-independent block of apoptosis by survivin in terminally differentiated neutrophils.
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.
Altznauer
Frank
F
Dept. of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland.
Martinelli
Sibylla
S
Yousefi
Shida
S
Thürig
Christine
C
Schmid
Inès
I
Conway
Edward M
EM
Schöni
Martin H
MH
Vogt
Peter
P
Mueller
Christoph
C
Fey
Martin F
MF
Zangemeister-Wittke
Uwe
U
Simon
Hans-Uwe
HU
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation; D002478:Cells, Cultured; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000473:pathology / Q000503:physiopathology; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology*; D009363:Neoplasm Proteins; D009367:Neoplasm Staging; D009369:Neoplasms / Q000473:pathology; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D011994:Recombinant Proteins; D000077022:Survivin
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D000077022:Survivin; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor