权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
9281705
负责人：
Vincenzo Coppola
金额：
$ 53.17万
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 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9281705
关键词：
Ablation Address Alternative Splicing Amino Acids Animal Model Animals Binding Biological Biology Breast Adenocarcinoma C-terminal Cell physiology Cellular biology Chromatin Complex DNA Polymerase II Data Databases Development Embryo Embryonic Development Epigenetic Process Exhibits Gene Targeting Genes Genetic Models Genetic Transcription 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 Reader Reagent Recruitment Activity Regulation Role Saccharomyces Saccharomyces cerevisiae Signal Transduction Specimen The Cancer Genome Atlas Tissues Transcription Elongation Transcriptional Elongation Factors 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）：Iws 1（与Spt 6相互作用）最初在酿酒酵母中被鉴定为Spt 6（一种组蛋白H3/H4伴侣）的结合伴侣。Spt 6还结合RNA Pol II大亚基的C末端结构域（CTD），随后后者在Ser 2处磷酸化。最近在哺乳动物细胞中的研究表明，在RNA Pol II的CTD上组装的Spt 6/Iws 1复合物包含两个额外的成员，Aly/REF，一种有助于核质RNA转运的衔接子，和SetD 2，一种组蛋白H3 K36三甲基转移酶。同样的研究表明，这种复合物有助于选择性RNA剪接。Tsichlis实验室的工作扩展了这些观察结果，表明在转录延伸过程中，SetD 2向Iws 1复合物的募集和组蛋白H3在K36处的三甲基化依赖于Akt 1和Akt 3对Iws 1的磷酸化。更重要的是，转录活性基因中Akt依赖的H3 K36三甲基化调节RNA剪接，并有助于人类非小细胞肺癌（NSCLC）的生物学。Tsichlis实验室最近的研究表明，Iws 1不仅可以调节RNA剪接，还可以调节RNA代谢的其他步骤。此外，它可能在非小细胞肺癌以外的肿瘤（包括乳腺腺癌和黑色素瘤）的发展和生物学中发挥重要作用。值得注意的是，IWS 1在乳腺癌中的作用也得到了TCGA数据库中原发性人类肿瘤的大规模数据的支持。要解决这些发现所产生的一些问题，需要建立一个小鼠遗传模型。这是由Coppola博士完成的，他建立了一种条件性Iws 1基因敲除小鼠。利用这种小鼠，Tsichlis和Coppola实验室将解决1）Iws 1在胚胎发育和成年动物组织生物学中的生理作用; 2）Iws 1在肿瘤发生中的作用; 3）Iws 1调节RNA代谢和其他细胞功能的分子机制。