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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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Analysis of Slik-Expressing CellsClones of cells expressing GFP and Slik expressed from EPg(2)20348 (top) or UAS-slik transgene (bottom) were induced at 48 ± 2 h AEL. Discs were dissected at 112 h AEL (EPg(2)20348) or 98 h AEL (UAS-slik), and cells were dissociated and analyzed by flow cytometry. Data for GFP and EP or transgene-expressing clonal cells are in green and nonexpressing control cells from the same discs are in red.(A) Cell sizes estimated by forward scatter values. Numbers represent the ratio of forward scatter values for GFP+/GFP− cells.(B) Distribution of cells in G1 (2C DNA content), S (2C–4C), and G2 (4C).
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pbio.0000035-g008: Analysis of Slik-Expressing CellsClones of cells expressing GFP and Slik expressed from EPg(2)20348 (top) or UAS-slik transgene (bottom) were induced at 48 ± 2 h AEL. Discs were dissected at 112 h AEL (EPg(2)20348) or 98 h AEL (UAS-slik), and cells were dissociated and analyzed by flow cytometry. Data for GFP and EP or transgene-expressing clonal cells are in green and nonexpressing control cells from the same discs are in red.(A) Cell sizes estimated by forward scatter values. Numbers represent the ratio of forward scatter values for GFP+/GFP− cells.(B) Distribution of cells in G1 (2C DNA content), S (2C–4C), and G2 (4C).

Mentions: To ask whether slik-driven tissue growth resulted from increased cell proliferation rather than from increased cell size (as results from activation of the insulin signaling pathway; Stocker and Hafen 2000), we performed flow cytometry on cells from dissociated discs. Slik-overexpressing cells showed a modest decrease in size (6% smaller than control cells using EPg(2)20348; 13% smaller using a stronger UAS-slik transgene; Figure 8A). Slik also had little effect on cell cycle profile (Figure 8B).


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

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

Analysis of Slik-Expressing CellsClones of cells expressing GFP and Slik expressed from EPg(2)20348 (top) or UAS-slik transgene (bottom) were induced at 48 ± 2 h AEL. Discs were dissected at 112 h AEL (EPg(2)20348) or 98 h AEL (UAS-slik), and cells were dissociated and analyzed by flow cytometry. Data for GFP and EP or transgene-expressing clonal cells are in green and nonexpressing control cells from the same discs are in red.(A) Cell sizes estimated by forward scatter values. Numbers represent the ratio of forward scatter values for GFP+/GFP− cells.(B) Distribution of cells in G1 (2C DNA content), S (2C–4C), and G2 (4C).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC261876&req=5

pbio.0000035-g008: Analysis of Slik-Expressing CellsClones of cells expressing GFP and Slik expressed from EPg(2)20348 (top) or UAS-slik transgene (bottom) were induced at 48 ± 2 h AEL. Discs were dissected at 112 h AEL (EPg(2)20348) or 98 h AEL (UAS-slik), and cells were dissociated and analyzed by flow cytometry. Data for GFP and EP or transgene-expressing clonal cells are in green and nonexpressing control cells from the same discs are in red.(A) Cell sizes estimated by forward scatter values. Numbers represent the ratio of forward scatter values for GFP+/GFP− cells.(B) Distribution of cells in G1 (2C DNA content), S (2C–4C), and G2 (4C).
Mentions: To ask whether slik-driven tissue growth resulted from increased cell proliferation rather than from increased cell size (as results from activation of the insulin signaling pathway; Stocker and Hafen 2000), we performed flow cytometry on cells from dissociated discs. Slik-overexpressing cells showed a modest decrease in size (6% smaller than control cells using EPg(2)20348; 13% smaller using a stronger UAS-slik transgene; Figure 8A). Slik also had little effect on cell cycle profile (Figure 8B).

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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