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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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Slik Acts via Raf to Control Cell Survival and Cell Proliferation(A and B) ptcGAL4 UAS-slik phenotype in different genetic backgrounds.(A) Quantification of the area between veins 3 and 4 as a function of total wing area. Control: wild-type flies. Other genotypes as indicated.(B) Detail of the vein 3–4 region in ptcGAL4 UAS-slik and Raf heterozygous phlEA75/+; ptcGAL4 UAS-slik wings. The multiple wing hair phenotype characteristic of Slik overexpression was suppressed when one copy of Raf was removed and the spacing between the veins was reduced.(C) Survival rates and assessment of the severity of the wing phenotypes in flies of the indicated genotypes.(D) TUNEL labeling of wing discs to visualize apoptotic cells. Genotypes as indicated. (E–G) slik1 mutant clones labeled by expression of GFP (green) and by the absence of Slik protein (red). Larval genotypes: UAS-CD8-GFP hsFlp; FRT42 Gal80/FRT42 slik1; Tub-Gal4/+. (F) Plus UAS-RafGOF. (G) Plus UAS-RlSEM. Lower panels show optical sections perpendicular to the plane of the epithelium. DAPI (blue) shown alone below.
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pbio.0000035-g010: Slik Acts via Raf to Control Cell Survival and Cell Proliferation(A and B) ptcGAL4 UAS-slik phenotype in different genetic backgrounds.(A) Quantification of the area between veins 3 and 4 as a function of total wing area. Control: wild-type flies. Other genotypes as indicated.(B) Detail of the vein 3–4 region in ptcGAL4 UAS-slik and Raf heterozygous phlEA75/+; ptcGAL4 UAS-slik wings. The multiple wing hair phenotype characteristic of Slik overexpression was suppressed when one copy of Raf was removed and the spacing between the veins was reduced.(C) Survival rates and assessment of the severity of the wing phenotypes in flies of the indicated genotypes.(D) TUNEL labeling of wing discs to visualize apoptotic cells. Genotypes as indicated. (E–G) slik1 mutant clones labeled by expression of GFP (green) and by the absence of Slik protein (red). Larval genotypes: UAS-CD8-GFP hsFlp; FRT42 Gal80/FRT42 slik1; Tub-Gal4/+. (F) Plus UAS-RafGOF. (G) Plus UAS-RlSEM. Lower panels show optical sections perpendicular to the plane of the epithelium. DAPI (blue) shown alone below.

Mentions: The slikKG04837 mutant produced a similar, but milder, phenotype than slik1. slikKG04837/slik1 flies showed a 13% decrease in viability. Nearly 40% of the wings in the surviving flies had phenotypes similar to those caused by slik1 mutant clones. Most showed curvature of the wing blade surface or small isolated vesicles (Figure 5E, arrow). However, 30% of affected wings showed a stronger phenotype characterized by accumulation of vesicles and reduction in wing size (Figure 5F). These defects correlated with an increased level of apoptosis in wing discs (see Figure 10D).


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

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

Slik Acts via Raf to Control Cell Survival and Cell Proliferation(A and B) ptcGAL4 UAS-slik phenotype in different genetic backgrounds.(A) Quantification of the area between veins 3 and 4 as a function of total wing area. Control: wild-type flies. Other genotypes as indicated.(B) Detail of the vein 3–4 region in ptcGAL4 UAS-slik and Raf heterozygous phlEA75/+; ptcGAL4 UAS-slik wings. The multiple wing hair phenotype characteristic of Slik overexpression was suppressed when one copy of Raf was removed and the spacing between the veins was reduced.(C) Survival rates and assessment of the severity of the wing phenotypes in flies of the indicated genotypes.(D) TUNEL labeling of wing discs to visualize apoptotic cells. Genotypes as indicated. (E–G) slik1 mutant clones labeled by expression of GFP (green) and by the absence of Slik protein (red). Larval genotypes: UAS-CD8-GFP hsFlp; FRT42 Gal80/FRT42 slik1; Tub-Gal4/+. (F) Plus UAS-RafGOF. (G) Plus UAS-RlSEM. Lower panels show optical sections perpendicular to the plane of the epithelium. DAPI (blue) shown alone below.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC261876&req=5

pbio.0000035-g010: Slik Acts via Raf to Control Cell Survival and Cell Proliferation(A and B) ptcGAL4 UAS-slik phenotype in different genetic backgrounds.(A) Quantification of the area between veins 3 and 4 as a function of total wing area. Control: wild-type flies. Other genotypes as indicated.(B) Detail of the vein 3–4 region in ptcGAL4 UAS-slik and Raf heterozygous phlEA75/+; ptcGAL4 UAS-slik wings. The multiple wing hair phenotype characteristic of Slik overexpression was suppressed when one copy of Raf was removed and the spacing between the veins was reduced.(C) Survival rates and assessment of the severity of the wing phenotypes in flies of the indicated genotypes.(D) TUNEL labeling of wing discs to visualize apoptotic cells. Genotypes as indicated. (E–G) slik1 mutant clones labeled by expression of GFP (green) and by the absence of Slik protein (red). Larval genotypes: UAS-CD8-GFP hsFlp; FRT42 Gal80/FRT42 slik1; Tub-Gal4/+. (F) Plus UAS-RafGOF. (G) Plus UAS-RlSEM. Lower panels show optical sections perpendicular to the plane of the epithelium. DAPI (blue) shown alone below.
Mentions: The slikKG04837 mutant produced a similar, but milder, phenotype than slik1. slikKG04837/slik1 flies showed a 13% decrease in viability. Nearly 40% of the wings in the surviving flies had phenotypes similar to those caused by slik1 mutant clones. Most showed curvature of the wing blade surface or small isolated vesicles (Figure 5E, arrow). However, 30% of affected wings showed a stronger phenotype characterized by accumulation of vesicles and reduction in wing size (Figure 5F). These defects correlated with an increased level of apoptosis in wing discs (see Figure 10D).

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.

Show MeSH
Related in: MedlinePlus