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Inflammation-associated cell cycle-independent block of apoptosis by survivin in terminally differentiated neutrophils.

Altznauer F, Martinelli S, Yousefi S, Thürig C, Schmid I, Conway EM, Schöni MH, Vogt P, Mueller C, Fey MF, Zangemeister-Wittke U, Simon HU - J. Exp. Med. (2004)

Bottom Line: In agreement with this current view, we found that survivin expression was high in immature neutrophils, which proliferate during differentiation.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.

View Article: PubMed Central - PubMed

Affiliation: Dept. of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland.

ABSTRACT
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.

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Survivin is predominantly localized in the cytoplasm of mature CF neutrophils and associated with low caspase-3 enzymatic activity. (A) Confocal microscopy. Survivin was readily detected in CF blood neutrophils where it is mostly localized in the cytoplasm. Bars, 10 μm. Three independent experiments are presented. (B) Caspase-3 activity assay. Neutrophils were analyzed after a 10-h culture period. Caspase-3 activity was much lower in CF compared with control neutrophils. In addition, when normal neutrophils were cultured in the presence of GM-CSF or G-CSF, significantly lower caspase-3 activity levels were measured. Values are means ± SEM of eleven (C), three (CF), four (G-CSF), and two (GM-CSF) independent experiments. ***, P < 0.001.
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fig6: Survivin is predominantly localized in the cytoplasm of mature CF neutrophils and associated with low caspase-3 enzymatic activity. (A) Confocal microscopy. Survivin was readily detected in CF blood neutrophils where it is mostly localized in the cytoplasm. Bars, 10 μm. Three independent experiments are presented. (B) Caspase-3 activity assay. Neutrophils were analyzed after a 10-h culture period. Caspase-3 activity was much lower in CF compared with control neutrophils. In addition, when normal neutrophils were cultured in the presence of GM-CSF or G-CSF, significantly lower caspase-3 activity levels were measured. Values are means ± SEM of eleven (C), three (CF), four (G-CSF), and two (GM-CSF) independent experiments. ***, P < 0.001.

Mentions: Elevated levels of survivin in peripheral blood neutrophils from patients with CF were confirmed by immunofluorescence and laser scan microscopy demonstrating that almost all neutrophils expressed survivin, predominantly in the cytoplasm (Fig. 6 A). Increased survivin levels in CF neutrophils correlated with decreased caspase-3–like DEVDase in 10-h neutrophil cultures (Fig. 6 B). Moreover, caspase-3–like DEVDase activity was much less in neutrophils stimulated with G-CSF or GM-CSF in vitro.


Inflammation-associated cell cycle-independent block of apoptosis by survivin in terminally differentiated neutrophils.

Altznauer F, Martinelli S, Yousefi S, Thürig C, Schmid I, Conway EM, Schöni MH, Vogt P, Mueller C, Fey MF, Zangemeister-Wittke U, Simon HU - J. Exp. Med. (2004)

Survivin is predominantly localized in the cytoplasm of mature CF neutrophils and associated with low caspase-3 enzymatic activity. (A) Confocal microscopy. Survivin was readily detected in CF blood neutrophils where it is mostly localized in the cytoplasm. Bars, 10 μm. Three independent experiments are presented. (B) Caspase-3 activity assay. Neutrophils were analyzed after a 10-h culture period. Caspase-3 activity was much lower in CF compared with control neutrophils. In addition, when normal neutrophils were cultured in the presence of GM-CSF or G-CSF, significantly lower caspase-3 activity levels were measured. Values are means ± SEM of eleven (C), three (CF), four (G-CSF), and two (GM-CSF) independent experiments. ***, P < 0.001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211817&req=5

fig6: Survivin is predominantly localized in the cytoplasm of mature CF neutrophils and associated with low caspase-3 enzymatic activity. (A) Confocal microscopy. Survivin was readily detected in CF blood neutrophils where it is mostly localized in the cytoplasm. Bars, 10 μm. Three independent experiments are presented. (B) Caspase-3 activity assay. Neutrophils were analyzed after a 10-h culture period. Caspase-3 activity was much lower in CF compared with control neutrophils. In addition, when normal neutrophils were cultured in the presence of GM-CSF or G-CSF, significantly lower caspase-3 activity levels were measured. Values are means ± SEM of eleven (C), three (CF), four (G-CSF), and two (GM-CSF) independent experiments. ***, P < 0.001.
Mentions: Elevated levels of survivin in peripheral blood neutrophils from patients with CF were confirmed by immunofluorescence and laser scan microscopy demonstrating that almost all neutrophils expressed survivin, predominantly in the cytoplasm (Fig. 6 A). Increased survivin levels in CF neutrophils correlated with decreased caspase-3–like DEVDase in 10-h neutrophil cultures (Fig. 6 B). Moreover, caspase-3–like DEVDase activity was much less in neutrophils stimulated with G-CSF or GM-CSF in vitro.

Bottom Line: In agreement with this current view, we found that survivin expression was high in immature neutrophils, which proliferate during differentiation.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.

View Article: PubMed Central - PubMed

Affiliation: Dept. of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus