The role of IWS1 in development and tumorigenesis

IWS1在发育和肿瘤发生中的作用

基本信息

批准号：
8946925
负责人：
Vincenzo Coppola
金额：
$ 54.47万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8946925
关键词：
Ablation Address Alternative Splicing Amino Acids Animal Model Animals Binding Biological Biology Breast Adenocarcinoma C-terminal Cell physiology Chromatin Complex DNA Polymerase II Data Databases Development Elongation Factor Embryo Embryonic Development Epigenetic Process Exhibits Gene Targeting Genes Genetic Models Histone H3 Histones Human Human Biology Knock-out Knockout Mice Laboratories Link Malignant Neoplasms Malignant neoplasm of lung Mammalian Cell Mammary gland Mediating Metabolism Molecular Molecular Chaperones Mus Non-Small-Cell Lung Carcinoma Oncogenes Orthologous Gene Phenotype Phosphorylation Physiological Play Process Proteins Publishing RNA RNA Polymerase II RNA Processing RNA Splicing RNA Transport RNA polymerase II largest subunit Reader Reagent Regulation Role Saccharomyces Saccharomyces cerevisiae Signal Transduction Specimen The Cancer Genome Atlas Tissues Transcription Elongation Transferase Tumor Biology Tumor Cell Biology Work Yeasts animal tissue base cancer stem cell chromatin modification epigenetic regulation genome-wide indexing malignant breast neoplasm mature animal melanocyte melanoma member migration mouse model neoplastic cell public health relevance self-renewal tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Iws1 (Interacts with Spt6) was originally identified in the yeast Saccharomyces Cerevisciae as a binding partner of Spt6, a histone H3/H4 chaperone. Spt6 also binds the C terminal domain (CTD) of the large subunit of RNA Pol II, following the phosphorylation of the latter at Ser2. Recent studies in mammalian cells revealed that the Spt6/Iws1 complex assembled on the CTD of RNA Pol II, contains two additional members, Aly/REF, an adaptor that contributes to nucleocytoplasmic RNA transport, and SetD2, a histone H3K36 trimethyl- transferase. The same studies showed that this complex contributes to alternative RNA splicing. Work in the Tsichlis laboratory extended these observations by showing that the recruitment of SetD2 to the Iws1 complex and the trimethylation of histone H3 at K36 during transcriptional elongation depend on the phosphorylation of Iws1 by Akt1 and Akt3. More important, the Akt-dependent H3K36 trimethylation in transcriptionally active genes regulates alternative RNA splicing and contributes to the biology of human non-small cell lung carcinomas (NSCLCs). More recent studies in the Tsichlis laboratory produced evidence that Iws1 may regulate not only RNA splicing, but also other steps in RNA metabolism. In addition, it may play an important role in the development and biology of tumors other than NSCLCs, including mammary adenocarcinomas and melanomas. It is noteworthy that the role of IWS1 in mammary adenocarcinomas is also supported by large scale data from primary human tumors in the TCGA database. Addressing some of the questions arising from these findings required the establishment of a mouse genetic model. This was accomplished by Dr Coppola who established a conditional Iws1 knockout mouse. Using this mouse, the Tsichlis and Coppola laboratories will address 1) the physiological role of Iws1 in embryonic development and in the biology of adult animal tissues; 2) the role of Iws1 in oncogenesis; and 3) the molecular mechanisms by which Iws1 regulates RNA metabolism and other cellular functions.

描述（由申请人提供）：Iws1（与 Spt6 相互作用）最初在酿酒酵母中被鉴定为 Spt6 的结合伴侣，Spt6 是组蛋白 H3/H4 伴侣，Spt6 也结合大亚基的 C 末端结构域 (CTD)。 RNA Pol II，后者在 Ser2 处磷酸化后，最近在哺乳动物细胞中的研究表明 Spt6/Iws1。在 RNA Pol II 的 CTD 上组装的复合物包含两个额外的成员：Aly/REF（一种有助于核细胞质 RNA 转运的接头）和 SetD2（一种组蛋白 H3K36 三甲基转移酶）。同样的研究表明，该复合物有助于替代 RNA 剪接。 Tsichlis 实验室的工作扩展了这些观察结果，表明在转录延伸依赖于 Akt1 和 Akt3 对 Iws1 的磷酸化，更重要的是，转录活性基因中依赖于 Akt 的 H3K36 三甲基化调节可变 RNA 剪接，并有助于人类非小细胞肺癌 (NSCLC) 的生物学。 Tsichlis 实验室的证据表明 Iws1 不仅可以调节 RNA 剪接，还可以调节 RNA 代谢的其他步骤。在非小细胞肺癌（NSCLC）以外的肿瘤（包括乳腺癌和黑色素瘤）的发展和生物学中的作用值得注意的是，TCGA 数据库中来自原发性人类肿瘤的大规模数据也支持了 IWS1 在乳腺癌中的作用。这些发现需要建立小鼠遗传模型，这是由 Coppola 博士完成的，他使用这种小鼠建立了条件性 Iws1 基因敲除小鼠。 Tsichlis 和 Coppola 实验室将研究 1) Iws1 在胚胎发育和成年动物组织生物学中的生理作用；2) Iws1 在肿瘤发生中的作用；以及 3) Iws1 调节 RNA 代谢和其他细胞功能的分子机制。。