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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-Induced Overgrowth in the Wing(A) Cuticle preparation of a ptcGAL4 adult wing.(B) Cuticle preparation of a ptcGAL4 UAS-slik adult wing.(C) Overlay of (A) (green) and (B) (red) aligned in the anterior margin. Note the increased separation of veins 3 and 4 in the center of the wing (arrow).(D) Cuticle preparation of a ptcGAL4 UAS-slik UAS-p35 adult wing. The separation of veins 3 and 4 was larger than in (C).(E) Measurement of the area enclosed by veins 3 and 4 in ptcGAL4 and ptcGAL4 UAS-slik wings. Error bars indicate standard deviation (*: p < 0.001 using a Student's t-test).
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pbio.0000035-g006: Slik-Induced Overgrowth in the Wing(A) Cuticle preparation of a ptcGAL4 adult wing.(B) Cuticle preparation of a ptcGAL4 UAS-slik adult wing.(C) Overlay of (A) (green) and (B) (red) aligned in the anterior margin. Note the increased separation of veins 3 and 4 in the center of the wing (arrow).(D) Cuticle preparation of a ptcGAL4 UAS-slik UAS-p35 adult wing. The separation of veins 3 and 4 was larger than in (C).(E) Measurement of the area enclosed by veins 3 and 4 in ptcGAL4 and ptcGAL4 UAS-slik wings. Error bars indicate standard deviation (*: p < 0.001 using a Student's t-test).

Mentions: We identified slik by its ability to promote overgrowth of the wing when expressed under GAL4 control. Overexpression of slik in the region between the third and fourth wing veins using ptcGAL4 caused overgrowth, increasing the distance between these veins (Figure 6A–6C). In larvae raised at 18°C, transgene-driven slik expression resulted in a 13% increase in the area bounded by veins 3 and 4 as a proportion of total wing area (p < 0.001; Figure 6E). When larvae were raised at 25°C, which normally results in higher levels of transgene activation, we saw only a 5% increase in area, suggesting that slik-driven overgrowth is offset by a counteracting process. This was examined in more detail in imaginal discs using green fluorescent protein (GFP) to mark cells overexpressing slik. We noted abnormal apoptotic cell death in the domain of slik and GFP expression, even when the larvae were raised at 18°C. Cellular and nuclear morphology were normal within the plane of the epithelium, but pyknotic nuclei were visible in GFP-expressing cells extruded below the epithelium (Figure 7A and 7B). High levels of activated caspase were also detected in this region (data not shown). These observations suggested that slik, like many oncogenes, promotes cell proliferation and apoptosis in parallel.


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

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

Slik-Induced Overgrowth in the Wing(A) Cuticle preparation of a ptcGAL4 adult wing.(B) Cuticle preparation of a ptcGAL4 UAS-slik adult wing.(C) Overlay of (A) (green) and (B) (red) aligned in the anterior margin. Note the increased separation of veins 3 and 4 in the center of the wing (arrow).(D) Cuticle preparation of a ptcGAL4 UAS-slik UAS-p35 adult wing. The separation of veins 3 and 4 was larger than in (C).(E) Measurement of the area enclosed by veins 3 and 4 in ptcGAL4 and ptcGAL4 UAS-slik wings. Error bars indicate standard deviation (*: p < 0.001 using a Student's t-test).
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Related In: Results  -  Collection

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pbio.0000035-g006: Slik-Induced Overgrowth in the Wing(A) Cuticle preparation of a ptcGAL4 adult wing.(B) Cuticle preparation of a ptcGAL4 UAS-slik adult wing.(C) Overlay of (A) (green) and (B) (red) aligned in the anterior margin. Note the increased separation of veins 3 and 4 in the center of the wing (arrow).(D) Cuticle preparation of a ptcGAL4 UAS-slik UAS-p35 adult wing. The separation of veins 3 and 4 was larger than in (C).(E) Measurement of the area enclosed by veins 3 and 4 in ptcGAL4 and ptcGAL4 UAS-slik wings. Error bars indicate standard deviation (*: p < 0.001 using a Student's t-test).
Mentions: We identified slik by its ability to promote overgrowth of the wing when expressed under GAL4 control. Overexpression of slik in the region between the third and fourth wing veins using ptcGAL4 caused overgrowth, increasing the distance between these veins (Figure 6A–6C). In larvae raised at 18°C, transgene-driven slik expression resulted in a 13% increase in the area bounded by veins 3 and 4 as a proportion of total wing area (p < 0.001; Figure 6E). When larvae were raised at 25°C, which normally results in higher levels of transgene activation, we saw only a 5% increase in area, suggesting that slik-driven overgrowth is offset by a counteracting process. This was examined in more detail in imaginal discs using green fluorescent protein (GFP) to mark cells overexpressing slik. We noted abnormal apoptotic cell death in the domain of slik and GFP expression, even when the larvae were raised at 18°C. Cellular and nuclear morphology were normal within the plane of the epithelium, but pyknotic nuclei were visible in GFP-expressing cells extruded below the epithelium (Figure 7A and 7B). High levels of activated caspase were also detected in this region (data not shown). These observations suggested that slik, like many oncogenes, promotes cell proliferation and apoptosis in parallel.

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