Limits...
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.

Show MeSH
Molecular Characterization of the slik Locus(A) Schematic representation of the slik region. Predicted genes are indicated.(B) Detailed view of the slik region. The insertion sites of EPg(2)23048 and KG04837 in the first intron and the extent of the slik1 deletion are indicated. l(2)K08003 is an allele of mov34. N, NotI; R, EcoRI.(C) Comparison of Slik with human SLK and LOK proteins. Numbers show sequence identity/similarity within the indicated domains. Predicted coiled-coil regions in the C-terminal domain are indicated by hatching.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC261876&req=5

pbio.0000035-g001: Molecular Characterization of the slik Locus(A) Schematic representation of the slik region. Predicted genes are indicated.(B) Detailed view of the slik region. The insertion sites of EPg(2)23048 and KG04837 in the first intron and the extent of the slik1 deletion are indicated. l(2)K08003 is an allele of mov34. N, NotI; R, EcoRI.(C) Comparison of Slik with human SLK and LOK proteins. Numbers show sequence identity/similarity within the indicated domains. Predicted coiled-coil regions in the C-terminal domain are indicated by hatching.

Mentions: Genes involved in regulating tissue growth were identified in a systematic overexpression screen (Hipfner et al. 2002). EPg(2)20348 caused increased growth of the posterior compartment of the wing by 6% without inducing pattern abnormalities when expressed under control of the enGAL4 driver. Though small in magnitude, this difference was reproducible and statistically significant. As will be shown below, considerably stronger growth effects were obtained when compensating apoptosis was prevented. To identify the gene overexpressed by EPg(2)20348, DNA flanking the single P-element insertion was sequenced. The EPg element was inserted in the first intron of CG4527, which we now name slik (Figure 1A and 1B). According to GADFLY (release 3), there are likely to be two transcripts produced by alternative splicing at the 3′ end of slik. The shorter of these, slik-RA, encodes a 1300 amino acid protein and is identical in sequence to the cDNA we assembled from expressed sequence tags (ESTs) LD34405 (AY119617) and GH20991 (AY058322). The slik-RB transcript contains three additional 3′ exons and is based on gene prediction and incomplete EST data.


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

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

Molecular Characterization of the slik Locus(A) Schematic representation of the slik region. Predicted genes are indicated.(B) Detailed view of the slik region. The insertion sites of EPg(2)23048 and KG04837 in the first intron and the extent of the slik1 deletion are indicated. l(2)K08003 is an allele of mov34. N, NotI; R, EcoRI.(C) Comparison of Slik with human SLK and LOK proteins. Numbers show sequence identity/similarity within the indicated domains. Predicted coiled-coil regions in the C-terminal domain are indicated by hatching.
© Copyright Policy
Related In: Results  -  Collection

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

pbio.0000035-g001: Molecular Characterization of the slik Locus(A) Schematic representation of the slik region. Predicted genes are indicated.(B) Detailed view of the slik region. The insertion sites of EPg(2)23048 and KG04837 in the first intron and the extent of the slik1 deletion are indicated. l(2)K08003 is an allele of mov34. N, NotI; R, EcoRI.(C) Comparison of Slik with human SLK and LOK proteins. Numbers show sequence identity/similarity within the indicated domains. Predicted coiled-coil regions in the C-terminal domain are indicated by hatching.
Mentions: Genes involved in regulating tissue growth were identified in a systematic overexpression screen (Hipfner et al. 2002). EPg(2)20348 caused increased growth of the posterior compartment of the wing by 6% without inducing pattern abnormalities when expressed under control of the enGAL4 driver. Though small in magnitude, this difference was reproducible and statistically significant. As will be shown below, considerably stronger growth effects were obtained when compensating apoptosis was prevented. To identify the gene overexpressed by EPg(2)20348, DNA flanking the single P-element insertion was sequenced. The EPg element was inserted in the first intron of CG4527, which we now name slik (Figure 1A and 1B). According to GADFLY (release 3), there are likely to be two transcripts produced by alternative splicing at the 3′ end of slik. The shorter of these, slik-RA, encodes a 1300 amino acid protein and is identical in sequence to the cDNA we assembled from expressed sequence tags (ESTs) LD34405 (AY119617) and GH20991 (AY058322). The slik-RB transcript contains three additional 3′ exons and is based on gene prediction and incomplete EST data.

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