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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: Strikingly, these cells reexpressed survivin upon granulocyte/macrophage colony-stimulating factor (CSF) or granulocyte CSF stimulation in vitro and under inflammatory conditions in vivo.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 expression in mature neutrophils under in vivo inflammatory conditions. (A) Immunohistochemistry. Cells morphologically representing neutrophils expressed survivin in tissue sections from patients with appendicitis. A control antibody did not stain the cells. (B). Confocal microscopy. Tissue neutrophils from patients with CF (n = 3), ulcerative colitis (n = 3), and appendicitis (n = 3) demonstrated evidence for survivin expression. Neutrophils were specifically detected using an anti-CD15 mAb. Note that in ulcerative colitis and appendicitis, some neutrophils were survivin negative (red cells in the overlay panel). Bars, 10 μm.
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fig5: Survivin expression in mature neutrophils under in vivo inflammatory conditions. (A) Immunohistochemistry. Cells morphologically representing neutrophils expressed survivin in tissue sections from patients with appendicitis. A control antibody did not stain the cells. (B). Confocal microscopy. Tissue neutrophils from patients with CF (n = 3), ulcerative colitis (n = 3), and appendicitis (n = 3) demonstrated evidence for survivin expression. Neutrophils were specifically detected using an anti-CD15 mAb. Note that in ulcerative colitis and appendicitis, some neutrophils were survivin negative (red cells in the overlay panel). Bars, 10 μm.

Mentions: To demonstrate survivin expression in neutrophils under in vivo conditions, we analyzed neutrophils in tissue sections of patients with three distinct inflammatory diseases. As assessed by immunohistochemistry, most neutrophils in the affected intestinal mucosa from patients with acute appendicitis stained positively using an antisurvivin antibody (Fig. 5 A). To more specifically measure protein expression in neutrophils, we also performed double immunofluorescence analysis. Infiltrating neutrophils were identified using an anti-CD15 mAb. In the lungs of CF patients, practically all neutrophils expressed survivin. In the intestine of ulcerative colitis patients, we counted ∼90% survivin-expressing neutrophils. In appendicitis, ∼75% of the infiltrating neutrophils were survivin positive (Fig. 5 B). These data suggest that high levels of survivin are not restricted to immature neutrophils and that mature neutrophils are able to reinduce high levels of survivin expression upon GM-CSF and/or G-CSF exposure under in vitro and in vivo conditions.


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 expression in mature neutrophils under in vivo inflammatory conditions. (A) Immunohistochemistry. Cells morphologically representing neutrophils expressed survivin in tissue sections from patients with appendicitis. A control antibody did not stain the cells. (B). Confocal microscopy. Tissue neutrophils from patients with CF (n = 3), ulcerative colitis (n = 3), and appendicitis (n = 3) demonstrated evidence for survivin expression. Neutrophils were specifically detected using an anti-CD15 mAb. Note that in ulcerative colitis and appendicitis, some neutrophils were survivin negative (red cells in the overlay panel). Bars, 10 μm.
© Copyright Policy
Related In: Results  -  Collection

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

fig5: Survivin expression in mature neutrophils under in vivo inflammatory conditions. (A) Immunohistochemistry. Cells morphologically representing neutrophils expressed survivin in tissue sections from patients with appendicitis. A control antibody did not stain the cells. (B). Confocal microscopy. Tissue neutrophils from patients with CF (n = 3), ulcerative colitis (n = 3), and appendicitis (n = 3) demonstrated evidence for survivin expression. Neutrophils were specifically detected using an anti-CD15 mAb. Note that in ulcerative colitis and appendicitis, some neutrophils were survivin negative (red cells in the overlay panel). Bars, 10 μm.
Mentions: To demonstrate survivin expression in neutrophils under in vivo conditions, we analyzed neutrophils in tissue sections of patients with three distinct inflammatory diseases. As assessed by immunohistochemistry, most neutrophils in the affected intestinal mucosa from patients with acute appendicitis stained positively using an antisurvivin antibody (Fig. 5 A). To more specifically measure protein expression in neutrophils, we also performed double immunofluorescence analysis. Infiltrating neutrophils were identified using an anti-CD15 mAb. In the lungs of CF patients, practically all neutrophils expressed survivin. In the intestine of ulcerative colitis patients, we counted ∼90% survivin-expressing neutrophils. In appendicitis, ∼75% of the infiltrating neutrophils were survivin positive (Fig. 5 B). These data suggest that high levels of survivin are not restricted to immature neutrophils and that mature neutrophils are able to reinduce high levels of survivin expression upon GM-CSF and/or G-CSF exposure under in vitro and in vivo conditions.

Bottom Line: Strikingly, these cells reexpressed survivin upon granulocyte/macrophage colony-stimulating factor (CSF) or granulocyte CSF stimulation in vitro and under inflammatory conditions in vivo.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