A Network of Genes Antagonistic to the LIN-35 Retinoblastoma Protein of Caenorhabditis elegans
A Network of Genes Antagonistic to the LIN-35 Retinoblastoma Protein of Caenorhabditis elegans
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DOI：
10.1534/genetics.112.140152
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发表时间：
2012-08-01
期刊：
影响因子：
3.3
通讯作者：
Fay, David S.
中科院分区：
文献类型：
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作者：
Polley, Stanley R. G.;Fay, David S.
秀丽隐杆线虫pRb的直系同源物，LIN-35，在广泛的细胞和发育过程中发挥作用。这包括LIN-35在肠道营养利用中的作用，它与锌指蛋白SLR-2冗余地进行。LIN-35的这种和其他冗余功能是在显示合成表型与lin-35丢失相关的突变的遗传筛选中鉴定的。为了探索LIN-35在肠道中的作用，我们进行了全基因组RNA干扰喂养筛选lin-35; slr-2早期幼虫停滞的抑制因子。在鉴定的26个抑制子中，17个属于三个功能类别：（1）核糖体生物发生基因，（2）线粒体线粒体蛋白酶抑制剂，和（3）染色质调节剂。进一步的表征表明，不同类别的抑制因子通过不同的分子机制起作用。我们还试验了林-35; SLR-2抑制子以及合成多叶表型的抑制子，以确定在抑制这些基因后可被抑制的LIN-35合成表型的谱。我们确定了19个基因，其中大部分是进化上保守的，可以抑制多种不相关的lin-35合成表型。我们的研究揭示了一个广泛拮抗LIN-35的基因网络，以及LIN-35在肠道和外阴发育中作用的特异性基因。多种lin-35表型的抑制基因可能成为抗癌治疗的候选靶点。此外，筛选抑制剂的表型不同的合成相互作用，共享一个共同的改变基因，可能被证明是一种新的和有效的方法，用于识别基因的活动是最直接相关的核心功能的共享基因。
The Caenorhabditis elegans pRb ortholog, LIN-35, functions in a wide range of cellular and developmental processes. This includes a role of LIN-35 in nutrient utilization by the intestine, which it carries out redundantly with SLR-2, a zinc-finger protein. This and other redundant functions of LIN-35 were identified in genetic screens for mutations that display synthetic phenotypes in conjunction with loss of lin-35. To explore the intestinal role of LIN-35, we conducted a genome-wide RNA-interference-feeding screen for suppressors of lin-35; slr-2 early larval arrest. Of the 26 suppressors identified, 17 fall into three functional classes: (1) ribosome biogenesis genes, (2) mitochondrial prohibitins, and (3) chromatin regulators. Further characterization indicates that different categories of suppressors act through distinct molecular mechanisms. We also tested lin-35; slr-2 suppressors, as well as suppressors of the synthetic multivulval phenotype, to determine the spectrum of lin-35-synthetic phenotypes that could be suppressed following inhibition of these genes. We identified 19 genes, most of which are evolutionarily conserved, that can suppress multiple unrelated lin-35-synthetic phenotypes. Our study reveals a network of genes broadly antagonistic to LIN-35 as well as genes specific to the role of LIN-35 in intestinal and vulval development. Suppressors of multiple lin-35 phenotypes may be candidate targets for anticancer therapies. Moreover, screening for suppressors of phenotypically distinct synthetic interactions, which share a common altered gene, may prove to be a novel and effective approach for identifying genes whose activities are most directly relevant to the core functions of the shared gene.