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（由应用程序提供）：IWS1（与SPT6相互作用）最初在酿酒酵母中识别为酿酒酵母作为SPT6的结合伴侣，SPT6是组蛋白H3/H4伴侣。 SPT6还结合了RNA POL II的大亚基的C末端结构域（CTD），后者在Ser2处的磷酸化。在哺乳动物细胞中的最新研究表明，SPT6/IWS1复合物组装在RNA POL II的CTD上，包含两个额外的成员Aly/Ref，一种适配器，该适配器有助于核细胞质RNA的转运，而SETD2（SETD2），一种组蛋白H3K3K3K3K3K3K36三甲基转移酶。同样的研究表明，这种复合物有助于替代RNA剪接。 Tsichlis实验室的工作通过表明SETD2募集到IWS1复合物以及转录伸长期间K36的组蛋白H3的三甲基化来扩展这些观察结果，这取决于AKT1和AKT3对IWS1的磷酸化。更重要的是，转录活性基因中依赖AKT的H3K36三甲基化调节替代性RNA剪接，并有助于人类非小细胞肺癌（NSCLCS）的生物学。在TSICHLIS实验室的最新研究产生了证据，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。此外，它可能在NSCLC以外的其他肿瘤的发育和生物学中起重要作用，包括乳腺腺癌和黑色素瘤。值得注意的是，IWS1在TCGA数据库中原发性人类肿瘤的大规模数据也支持了IWS1在乳腺腺癌中的作用。解决这些发现引起的一些问题需要建立小鼠遗传模型。这是由Coppola博士完成的，他建立了有条件的IWS1敲除鼠标。使用此小鼠，Tsichlis和Coppola实验室将解决1）IWS1在胚胎发育和成年动物组织的生物学中的身体作用； 2）IWS1在肿瘤发生中的作用； 3）IWS1调节RNA代谢和其他细胞功能的分子机制。