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The Drosophila sterile-20 kinase slik controls cell proliferation and apoptosis during imaginal disc development.

Hipfner DR, Cohen SM - PLoS Biol. (2003)

Bottom Line: Tumor-like tissue overgrowth results when apoptosis is prevented.Activation of Raf can compensate for the lack of Slik and support cell survival, but activation of ERK cannot.We suggest that Slik mediates growth and survival cues to promote cell proliferation and control cell survival during Drosophila development.

View Article: PubMed Central - PubMed

Affiliation: European Molecular Biology Laboratory, Heidelberg, Germany.

ABSTRACT
Cell proliferation and programmed cell death are closely controlled during animal development. Proliferative stimuli generally also induce apoptosis, and anti-apoptotic factors are required to allow net cell proliferation. Genetic studies in Drosophila have led to identification of a number of genes that control both processes, providing new insights into the mechanisms that coordinate cell growth, proliferation, and death during development and that fail to do so in diseases of cell proliferation. We present evidence that the Drosophila Sterile-20 kinase Slik promotes cell proliferation and controls cell survival. At normal levels, Slik provides survival cues that prevent apoptosis. Cells deprived of Slik activity can grow, divide, and differentiate, but have an intrinsic survival defect and undergo apoptosis even under conditions in which they are not competing with normal cells for survival cues. Like some oncogenes, excess Slik activity stimulates cell proliferation, but this is compensated for by increased cell death. Tumor-like tissue overgrowth results when apoptosis is prevented. We present evidence that Slik acts via Raf, but not via the canonical ERK pathway. Activation of Raf can compensate for the lack of Slik and support cell survival, but activation of ERK cannot. We suggest that Slik mediates growth and survival cues to promote cell proliferation and control cell survival during Drosophila development.

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Nonautonomous Stimulation of Cell Proliferation by Slik-Expressing Cells(A, D, G) ptcGAL4 UAS-GFP wing discs. (B, E, H) ptcGAL4 UAS-slik UAS-GFP UAS-p35 wing discs. (C, F, I) ptcGAL4 UAS-slikkd UAS-GFP UAS-p35 wing discs. (A–C, G–I) BrdU incorporation (red). (A–C) Projections of several optical sections. (G–I) Sections of the overlying peripodial layer. (D–F) Peripodial cell nuclei visualized by DAPI. Arrows show high nuclear density above the ptcGAL4 UAS-GFP stripe in the columnar epithelium in (E) and (F). Asterisks indicate the peripodial extension of the ptcGAL4 stripe. (H and I) Cells in this region have incorporated more BrdU than control disc in (G).
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pbio.0000035-g009: Nonautonomous Stimulation of Cell Proliferation by Slik-Expressing Cells(A, D, G) ptcGAL4 UAS-GFP wing discs. (B, E, H) ptcGAL4 UAS-slik UAS-GFP UAS-p35 wing discs. (C, F, I) ptcGAL4 UAS-slikkd UAS-GFP UAS-p35 wing discs. (A–C, G–I) BrdU incorporation (red). (A–C) Projections of several optical sections. (G–I) Sections of the overlying peripodial layer. (D–F) Peripodial cell nuclei visualized by DAPI. Arrows show high nuclear density above the ptcGAL4 UAS-GFP stripe in the columnar epithelium in (E) and (F). Asterisks indicate the peripodial extension of the ptcGAL4 stripe. (H and I) Cells in this region have incorporated more BrdU than control disc in (G).

Mentions: To verify that slik-induced tissue overgrowth resulted from increased cell proliferation, we used BrdU incorporation to label cells that had undergone DNA replication. During a 1-h labeling period cells in wing discs from control ptcGAL4, UAS-GFP larvae incorporated BrdU in a uniformly random pattern, typical of normal wing discs (Figure 9A). In contrast, there was a considerable increase in the number of cells that incorporated BrdU in the center of discs overexpressing slik under ptcGAL4 control (Figure 9B). We noted that the region of increased proliferation was centered on the stripe of cells expressing the GAL4 driver, but was not limited to it.


The Drosophila sterile-20 kinase slik controls cell proliferation and apoptosis during imaginal disc development.

Hipfner DR, Cohen SM - PLoS Biol. (2003)

Nonautonomous Stimulation of Cell Proliferation by Slik-Expressing Cells(A, D, G) ptcGAL4 UAS-GFP wing discs. (B, E, H) ptcGAL4 UAS-slik UAS-GFP UAS-p35 wing discs. (C, F, I) ptcGAL4 UAS-slikkd UAS-GFP UAS-p35 wing discs. (A–C, G–I) BrdU incorporation (red). (A–C) Projections of several optical sections. (G–I) Sections of the overlying peripodial layer. (D–F) Peripodial cell nuclei visualized by DAPI. Arrows show high nuclear density above the ptcGAL4 UAS-GFP stripe in the columnar epithelium in (E) and (F). Asterisks indicate the peripodial extension of the ptcGAL4 stripe. (H and I) Cells in this region have incorporated more BrdU than control disc in (G).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC261876&req=5

pbio.0000035-g009: Nonautonomous Stimulation of Cell Proliferation by Slik-Expressing Cells(A, D, G) ptcGAL4 UAS-GFP wing discs. (B, E, H) ptcGAL4 UAS-slik UAS-GFP UAS-p35 wing discs. (C, F, I) ptcGAL4 UAS-slikkd UAS-GFP UAS-p35 wing discs. (A–C, G–I) BrdU incorporation (red). (A–C) Projections of several optical sections. (G–I) Sections of the overlying peripodial layer. (D–F) Peripodial cell nuclei visualized by DAPI. Arrows show high nuclear density above the ptcGAL4 UAS-GFP stripe in the columnar epithelium in (E) and (F). Asterisks indicate the peripodial extension of the ptcGAL4 stripe. (H and I) Cells in this region have incorporated more BrdU than control disc in (G).
Mentions: To verify that slik-induced tissue overgrowth resulted from increased cell proliferation, we used BrdU incorporation to label cells that had undergone DNA replication. During a 1-h labeling period cells in wing discs from control ptcGAL4, UAS-GFP larvae incorporated BrdU in a uniformly random pattern, typical of normal wing discs (Figure 9A). In contrast, there was a considerable increase in the number of cells that incorporated BrdU in the center of discs overexpressing slik under ptcGAL4 control (Figure 9B). We noted that the region of increased proliferation was centered on the stripe of cells expressing the GAL4 driver, but was not limited to it.

Bottom Line: Tumor-like tissue overgrowth results when apoptosis is prevented.Activation of Raf can compensate for the lack of Slik and support cell survival, but activation of ERK cannot.We suggest that Slik mediates growth and survival cues to promote cell proliferation and control cell survival during Drosophila development.

View Article: PubMed Central - PubMed

Affiliation: European Molecular Biology Laboratory, Heidelberg, Germany.

ABSTRACT
Cell proliferation and programmed cell death are closely controlled during animal development. Proliferative stimuli generally also induce apoptosis, and anti-apoptotic factors are required to allow net cell proliferation. Genetic studies in Drosophila have led to identification of a number of genes that control both processes, providing new insights into the mechanisms that coordinate cell growth, proliferation, and death during development and that fail to do so in diseases of cell proliferation. We present evidence that the Drosophila Sterile-20 kinase Slik promotes cell proliferation and controls cell survival. At normal levels, Slik provides survival cues that prevent apoptosis. Cells deprived of Slik activity can grow, divide, and differentiate, but have an intrinsic survival defect and undergo apoptosis even under conditions in which they are not competing with normal cells for survival cues. Like some oncogenes, excess Slik activity stimulates cell proliferation, but this is compensated for by increased cell death. Tumor-like tissue overgrowth results when apoptosis is prevented. We present evidence that Slik acts via Raf, but not via the canonical ERK pathway. Activation of Raf can compensate for the lack of Slik and support cell survival, but activation of ERK cannot. We suggest that Slik mediates growth and survival cues to promote cell proliferation and control cell survival during Drosophila development.

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