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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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Growth and Survival Defects in slik Mutant Clones(A) Wing imaginal disc with several homozygous slik1 mutant clones and homozygous wild-type twin clones (part of a leg disc is visible at upper right). The homozygous wild-type and mutant cells are produced in the same cell division, so differences in size reflect differences in growth or cell survival after clone induction. Homozygous slik1 mutant cells lack the βGAL marker protein and are unlabeled (black). Homozygous wild-type cells have two copies of the marker and appear brighter than heterozygous slik1/+ cells.(B) Area measurements of 48 pairs of homozygous slik1 mutant and wild-type twin clones.(C and D) Wing disc with a large homozygous Minute+ slik1 mutant clone produced in a Minute heterozygous background. Slik protein is shown in red. Blue shows DAPI-labeled nuclei. (C) and (D) are different optical sections of the same disc. (D) shows the pyknotic nuclei below the epithelial layer.(E and F) Wing discs with large homozygous Minute+ slik1 mutant clones. Red shows a single optical section showing Slik protein. Green shows a projection of several optical sections showing TUNEL labeling to visualize apoptotic cells. (F) Mid-third instar disc.(G) DAPI and TUNEL labeling of a slik1 homozygous mutant wing disc.
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pbio.0000035-g003: Growth and Survival Defects in slik Mutant Clones(A) Wing imaginal disc with several homozygous slik1 mutant clones and homozygous wild-type twin clones (part of a leg disc is visible at upper right). The homozygous wild-type and mutant cells are produced in the same cell division, so differences in size reflect differences in growth or cell survival after clone induction. Homozygous slik1 mutant cells lack the βGAL marker protein and are unlabeled (black). Homozygous wild-type cells have two copies of the marker and appear brighter than heterozygous slik1/+ cells.(B) Area measurements of 48 pairs of homozygous slik1 mutant and wild-type twin clones.(C and D) Wing disc with a large homozygous Minute+ slik1 mutant clone produced in a Minute heterozygous background. Slik protein is shown in red. Blue shows DAPI-labeled nuclei. (C) and (D) are different optical sections of the same disc. (D) shows the pyknotic nuclei below the epithelial layer.(E and F) Wing discs with large homozygous Minute+ slik1 mutant clones. Red shows a single optical section showing Slik protein. Green shows a projection of several optical sections showing TUNEL labeling to visualize apoptotic cells. (F) Mid-third instar disc.(G) DAPI and TUNEL labeling of a slik1 homozygous mutant wing disc.

Mentions: To evaluate the cellular basis for the larval growth defects, we examined the requirement for slik in diploid cells of the imaginal discs. Antibody labeling showed that Slik protein is expressed at a uniform level in the discs. We generated mosaic animals bearing slik mutant clones using FLP/FRT-mediated recombination. slik mutant clones were smaller than their simultaneously generated wild-type twin clones in the wing disc (Figure 3A). Mutant clones generated at 48 ± 2 h covered on average only 44% the area of the corresponding wild-type twin clones (Figure 3B) and rarely reached a large size. When clones were induced earlier, many discs were found to contain wild-type twinspots with no mutant clones, indicating that the slik mutant cells were eliminated. We did not observe any position-dependent effects on clonal growth, suggesting that slik function is required in all wing disc cells.


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

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

Growth and Survival Defects in slik Mutant Clones(A) Wing imaginal disc with several homozygous slik1 mutant clones and homozygous wild-type twin clones (part of a leg disc is visible at upper right). The homozygous wild-type and mutant cells are produced in the same cell division, so differences in size reflect differences in growth or cell survival after clone induction. Homozygous slik1 mutant cells lack the βGAL marker protein and are unlabeled (black). Homozygous wild-type cells have two copies of the marker and appear brighter than heterozygous slik1/+ cells.(B) Area measurements of 48 pairs of homozygous slik1 mutant and wild-type twin clones.(C and D) Wing disc with a large homozygous Minute+ slik1 mutant clone produced in a Minute heterozygous background. Slik protein is shown in red. Blue shows DAPI-labeled nuclei. (C) and (D) are different optical sections of the same disc. (D) shows the pyknotic nuclei below the epithelial layer.(E and F) Wing discs with large homozygous Minute+ slik1 mutant clones. Red shows a single optical section showing Slik protein. Green shows a projection of several optical sections showing TUNEL labeling to visualize apoptotic cells. (F) Mid-third instar disc.(G) DAPI and TUNEL labeling of a slik1 homozygous mutant wing disc.
© Copyright Policy
Related In: Results  -  Collection

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

pbio.0000035-g003: Growth and Survival Defects in slik Mutant Clones(A) Wing imaginal disc with several homozygous slik1 mutant clones and homozygous wild-type twin clones (part of a leg disc is visible at upper right). The homozygous wild-type and mutant cells are produced in the same cell division, so differences in size reflect differences in growth or cell survival after clone induction. Homozygous slik1 mutant cells lack the βGAL marker protein and are unlabeled (black). Homozygous wild-type cells have two copies of the marker and appear brighter than heterozygous slik1/+ cells.(B) Area measurements of 48 pairs of homozygous slik1 mutant and wild-type twin clones.(C and D) Wing disc with a large homozygous Minute+ slik1 mutant clone produced in a Minute heterozygous background. Slik protein is shown in red. Blue shows DAPI-labeled nuclei. (C) and (D) are different optical sections of the same disc. (D) shows the pyknotic nuclei below the epithelial layer.(E and F) Wing discs with large homozygous Minute+ slik1 mutant clones. Red shows a single optical section showing Slik protein. Green shows a projection of several optical sections showing TUNEL labeling to visualize apoptotic cells. (F) Mid-third instar disc.(G) DAPI and TUNEL labeling of a slik1 homozygous mutant wing disc.
Mentions: To evaluate the cellular basis for the larval growth defects, we examined the requirement for slik in diploid cells of the imaginal discs. Antibody labeling showed that Slik protein is expressed at a uniform level in the discs. We generated mosaic animals bearing slik mutant clones using FLP/FRT-mediated recombination. slik mutant clones were smaller than their simultaneously generated wild-type twin clones in the wing disc (Figure 3A). Mutant clones generated at 48 ± 2 h covered on average only 44% the area of the corresponding wild-type twin clones (Figure 3B) and rarely reached a large size. When clones were induced earlier, many discs were found to contain wild-type twinspots with no mutant clones, indicating that the slik mutant cells were eliminated. We did not observe any position-dependent effects on clonal growth, suggesting that slik function is required in all wing disc cells.

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