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

David R Hipfner,Stephen M Cohen,Matthew P Scott Matthew P Scott

doi:10.1371/journal.pbio.0000035

David R Hipfner, Stephen M Cohen + Show 1 more

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https://doi.org/10.1371/journal.pbio.0000035

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Journal: PLoS biology	Publication Date: Nov 1, 2003
Citations: 87	License type: CC BY 4.0

Affiliation: European Molecular Biology Laboratory

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.

Highlights

Growth of tissues and organs during animal development involves careful coordination of the rates of cell proliferation, cell death, and differentiation (Neufeld et al 1998; Conlon and Raff 1999)
We suggest that Slik activity mediates growth and survival cues to promote cell proliferation and cell survival and present evidence that this depends on the activation of the MAP kinase kinase kinase (MAP3K) Raf, but not via the canonical extracellular signal-regulated kinase (ERK) MAP kinase (MAPK) pathway
Taken together with the finding that expression of activated ERK cannot rescue the slik mutant survival defect in vivo, these findings suggest that Raf does not act via the canonical ERK MAPK pathway to mediate Slik’s activity in supporting cell survival and promoting cell proliferation

Summary

Introduction

Growth of tissues and organs during animal development involves careful coordination of the rates of cell proliferation, cell death, and differentiation (Neufeld et al 1998; Conlon and Raff 1999). Ras, myc, TSC1/TSC2, and genes in the insulin pathway have been implicated primarily in control of cellular growth rates (Johnston et al 1999; Prober and Edgar 2000; Saucedo and Edgar 2002 [reviewed in Oldham and Hafen 2003]). Cell growth and division rates are normally well coordinated, but excess activity of the insulin pathway, Ras, or Myc can cause cells to grow faster than they divide, leading to cellular overgrowth and concomitant tissue overgrowth. Cyclin D and Cdk act together to promote coordinated cellular growth and cell division, leading to net cell proliferation (Datar et al 2000; Meyer et al 2000). The bantam gene encodes a microRNA that promotes net cell proliferation (Hipfner et al 2002; Brennecke et al 2003). The bantam gene encodes a microRNA that promotes net cell proliferation (Hipfner et al 2002; Brennecke et al 2003). bantam prevents apoptosis by regulating translation of the apoptosis-inducing gene hid (Brennecke et al 2003)

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