Morphogenesis Group, Ludwig Institute for Cancer Research (UCL Branch), Riding House Street, London, W1W 7BS, UK.
Genome Biol. 2009 Feb 12;10(2):R20. doi: 10.1186/gb-2009-10-2-r20.
In multicellular animals, cell size is controlled by a limited set of conserved intracellular signaling pathways, which when deregulated contribute to tumorigenesis by enabling cells to grow outside their usual niche. To delineate the pathways controlling this process, we screened a genome-scale, image-based Drosophila RNA interference dataset for double-stranded RNAs that reduce the average size of adherent S2R+ cells.
Automated analysis of images from this RNA interference screen identified the receptor tyrosine kinase Pvr, Ras pathway components and several novel genes as regulators of cell size. Significantly, Pvr/Ras signaling also affected the size of other Drosophila cell lines and of larval hemocytes. A detailed genetic analysis of this growth signaling pathway revealed a role for redundant secreted ligands, Pvf2 and Pvf3, in the establishment of an autocrine growth signaling loop. Downstream of Ras1, growth signaling was found to depend on parallel mitogen-activated protein kinase (MAPK) and phospho-inositide-3-kinase (PI3K) signaling modules, as well as the Tor pathway.
This automated genome-wide screen identifies autocrine Pvf/Pvr signaling, upstream of Ras, MAPK and PI3K, as rate-limiting for the growth of immortalized fly cells in culture. Since, Pvf2/3 and Pvr show mutually exclusive in vivo patterns of gene expression, these data suggest that co-expression of this receptor-ligand pair plays a key role in driving cell autonomous growth during the establishment of Drosophila cell lines, as has been suggested to occur during tumor development.
在多细胞动物中，细胞大小由一组有限的保守细胞内信号通路控制，这些信号通路失调会导致肿瘤发生，使细胞能够在其通常的龛位之外生长。为了描绘控制这一过程的途径，我们筛选了一个基于基因组规模的、基于图像的 Drosophila RNA 干扰数据集，以寻找降低贴壁 S2R+细胞平均大小的双链 RNA。
对该 RNA 干扰筛选的图像进行自动分析，鉴定出受体酪氨酸激酶 Pvr、Ras 途径成分和几个新基因作为细胞大小的调节剂。值得注意的是，Pvr/Ras 信号还影响其他 Drosophila 细胞系和幼虫血细胞的大小。对该生长信号通路的详细遗传分析表明，冗余分泌配体 Pvf2 和 Pvf3 在建立自分泌生长信号环中起作用。在 Ras1 下游，发现生长信号依赖于平行的丝裂原激活蛋白激酶（MAPK）和磷酸肌醇-3-激酶（PI3K）信号模块，以及 Tor 途径。
这个自动化的全基因组筛选确定了自分泌的 Pvf/Pvr 信号，在 Ras、MAPK 和 PI3K 的上游，是培养中永生蝇细胞生长的限速因素。由于 Pvf2/3 和 Pvr 在体内表现出相互排斥的基因表达模式，这些数据表明，这种受体-配体对的共表达在建立 Drosophila 细胞系过程中驱动细胞自主生长中起着关键作用，正如在肿瘤发生过程中所提出的那样。
