High throughput RNAi screening identifies ID1 as a synthetic sick/lethal gene interacting with the common TP53 mutation R175H.
High throughput RNAi screening identifies ID1 as a synthetic sick/lethal gene interacting with the common TP53 mutation R175H.
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DOI：
10.3892/or.2013.2953
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发表时间：
2014-03
期刊：
影响因子：
4.2
通讯作者：
Ishioka C
中科院分区：
文献类型：
--
作者：
Imai H;Kato S;Sakamoto Y;Kakudo Y;Shimodaira H;Ishioka C
TP 53突变（R175 H）是人类癌症中最常见的突变之一。寻找导致R175 H表达的癌细胞的基因是癌症治疗的一个非常有吸引力的策略。本研究的目的是鉴定与R175 H相互作用的合成的致病/致死基因。利用慢病毒条形码的shRNA文库和在SF 126人胶质母细胞瘤细胞系（SF 126-tet-R175 H）中表达的四环素诱导的R175 H，我们进行了高通量筛选以鉴定在表达R175 H的细胞中诱导合成性疾病/致死的候选基因。我们确定了906个候选基因的支持，可能会导致加速细胞生长抑制R175 H的存在。分化抑制因子1（Inhibitor of differentiation 1，ID 1）是候选基因之一，siRNA抑制ID 1可加速瞬时表达和内源性表达R175 H的细胞的生长抑制，但在TP 53缺失细胞系或其他常见的p53突变体（如R273 H）中则无此作用。流式细胞仪分析表明，ID 1抑制导致G1期阻滞，R175 H的表达加速了阻滞。ID 1是一种与R175 H相互作用的合成致病/致死基因，被认为是R175 H表达细胞中癌症治疗的新分子靶点。
The TP53 mutation (R175H) is one of the most common mutations in human cancer. It is a highly attractive strategy for cancer therapy to find the genes that lead the R175H-expressing cancer cells. The aim of this study was to identify the synthetic sick/lethal gene interacting with R175H. Using lentiviral bar-coded comprehensive shRNA library and a tetracycline-inducible R175H expressed in the SF126 human glioblastoma cell line (SF126-tet-R175H), we conducted high-throughput screening to identify the candidate genes that induce synthetic sickness/lethality in R175H-expressing cells. We identified 906 candidate gene suppressions that may lead to accelerated cell growth inhibition in the presence of R175H. Inhibitor of differentiation 1 (ID1) was one of the candidate genes, and its suppression by siRNA resulted in the acceleration of growth inhibition in cell lines both transiently and endogenously expressing R175H but not in TP53-null cell lines or other common p53 mutants (such as R273H). Flow cytometry analysis showed that ID1 suppression resulted in G1 arrest, and the arrest was accelerated by the expression of R175H. ID1 is a synthetic sick/lethal gene that interacts with R175H and is considered to be a novel molecular target for cancer therapy in R175H-expressing cells.
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影响因子：
3.9
作者：
Olivier, M;Eeles, R;Hainaut, P
通讯作者：
Hainaut, P
影响因子：
64.5
作者：
BENEZRA, R;DAVIS, RL;WEINTRAUB, H
通讯作者：
WEINTRAUB, H
影响因子：
11.2
作者：
Kakudo, Y;Shibata, H;Ishioka, C
通讯作者：
Ishioka, C
影响因子：
8.8
作者：
Canaani, D.
通讯作者：
Canaani, D.
全基因组的RNAi筛查鉴定了与RAS癌基因的多种合成致死相互作用。
影响因子：
64.5
作者：
Luo J;Emanuele MJ;Li D;Creighton CJ;Schlabach MR;Westbrook TF;Wong KK;Elledge SJ
通讯作者：
Elledge SJ