Abstract
Awd, the Drosophila homologue of NME1/2 metastasis suppressors, plays key roles in many signaling pathways. Mosaic analysis of the null awdJ2A4 allele showed that loss of awd gene function blocks Notch signaling and the expression of its target genes including the Wingless (Wg/Wnt1) morphogen. We also showed that RNA interference (RNAi)-mediated awd silencing (awdi) in larval wing disc leads to chromosomal instability (CIN) and to Jun amino-terminal kinases (JNK)-mediated cell death. Here we show that this cell death is independent of p53 activity. Based on our previous finding showing that forced survival of awdi-CIN cells leads to aneuploidy without the hyperproliferative effect, we investigated the Wg expression in awdi wing disc cells. Interestingly, the Wg protein is expressed in its correct dorso-ventral domain but shows an altered cellular distribution which impairs its signaling. Further, we show that RNAi-mediated knock down of awd in wing discs does not affect Notch signaling. Thus, our analysis of the hypomorphic phenotype arising from awd downregulation uncovers a dose-dependent effect of Awd in Notch and Wg signaling.
Highlights
The Drosophila abnormal wing disc gene is the only homolog of NME1/2 genes identified to date [1,2]
We find that the block of p53 activity in awdi wing disc cells does not enhance apoptotic cell death suggesting that awdi does not induce the p53-mediated response to repair DNA damage
We analyzed the effect of awd downregulation in the wing disc, the primordium of Drosophila adult wing, which is a powerful model for studying tumorigenic growth [19] (Figure 1A)
Summary
The Drosophila abnormal wing disc (awd) gene is the only homolog of NME1/2 genes identified to date [1,2]. The NME1 gene, the first identified metastasis suppressor gene [2], and the NME2 gene are the ones most often implicated in tumor progression. The NME proteins have several biochemical functions and their tumorigenic role is far to be completely understood. Metastasis suppression was found in a variety of tumor types including melanoma, breast, ovarian, colon and hepatocellular carcinomas [4]. In these malignancies, NME expression is inversely correlated with poor survival and tumor grade. Extracellular NME proteins have been detected in the medium of cell lines and in human body fluids where their levels vary in different pathological conditions [7]. The physiological function of the secreted NME proteins is still a matter of debate
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