A genome-wide RNAi screen for polypeptides that alter rpS6 phosphorylation.
A genome-wide RNAi screen for polypeptides that alter rpS6 phosphorylation.
复制标题
对改变 rpS6 磷酸化的多肽进行全基因组 RNAi 筛选。
DOI：
10.1007/978-1-61779-430-8_11
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Avruch,Joseph
中科院分区：
文献类型：
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作者：
Papageorgiou,Angela;Avruch,Joseph
哺乳动物雷帕霉素靶蛋白（mTOR）是一种巨大的蛋白激酶，控制细胞增殖、生长和代谢。mTOR受营养可利用性、有丝分裂原和应激调节，并通过两种独立调节的异聚物复合物起作用。我们试图利用rnai诱导的细胞多肽耗竭的全基因组方法，确定维持氨基酸依赖性、雷帕霉素抑制复合物mTOR复合物1 （mTORC1）活性所必需的细胞成分。我们使用胰腺导管腺癌（PDAC）细胞系Mia-PaCa进行筛查；与许多胰腺癌一样，这些细胞表现出mTORC1的组成性激活。PDAC是最常见的胰腺癌，尽管目前采用非特异性和靶向治疗，其5年生存率仍为3-5%。虽然雷帕霉素相关的mTOR抑制剂尚未表现出令人鼓舞的临床反应，但现在很明显，这类化合物只能部分抑制mTORC1。识别先前未被发现的维持mTORC1活性所需的蛋白质可能提供新的靶点，并导致胰腺癌有益疗法的发展。
Mammalian target of rapamycin (mTOR) is a giant protein kinase that controls cell proliferation, growth, and metabolism. mTOR is regulated by nutrient availability, by mitogens, and by stress, and operates through two independently regulated hetero-oligomeric complexes. We have attempted to identify the cellular components necessary to maintain the activity of mTOR complex 1 (mTORC1), the amino acid-dependent, rapamycin-inhibitable complex, using a whole genome approach involving RNAi-induced depletion of cellular polypeptides. We have used a pancreatic ductal adenocarcinoma (PDAC) cell line, Mia-PaCa for this screen; as with many pancreatic cancers, these cells exhibit constitutive activation of mTORC1. PDAC is the most common form of pancreatic cancer and the 5-year survival rate remains 3–5% despite current nonspecific and targeted therapies. Although rapamycin-related mTOR inhibitors have yet to demonstrate encouraging clinical responses, it is now evident that this class of compounds is capable of only partial mTORC1 inhibition. Identifying previously unappreciated proteins needed for maintenance of mTORC1 activity may provide new targets and lead to the development of beneficial therapies for pancreatic cancer.