Characterization of the SUMO ligase PIAS1 in tumor progression and metastasis

SUMO 连接酶 PIAS1 在肿瘤进展和转移中的表征

基本信息

批准号：
8914404
负责人：
Jerfiz D Constanzo
金额：
$ 2.34万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-16 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8914404
关键词：
Acute Promyelocytic Leukemia Affect Apoptosis Apoptotic Biological Assay Breast Cancer Cell Breast Cancer cell line Cell Adhesion Molecules Cell Death Cell Line Cell Proliferation Cell Shape Cell Survival Cell model Cells Cellular Morphology Cellular Stress Contact Inhibition Cytoskeleton Data Development Disease Ectopic Expression Embryo Event Failure Family Family member Fibroblasts Focal Adhesion Kinase 1 Focal Adhesions Foundations Genetic Goals Guanosine Triphosphate Phosphohydrolases Health Human Immigration In Vitro Knockout Mice Ligase Malignant Neoplasms Malignant neoplasm of lung Mediating Mus Mutation Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Null Lymphocytes PIAS3 Gene Play Predisposition Proteins Regulation Research Rest Role Signal Transduction Small Interfering RNA Stimulus Testing Tumor Burden Tumor Suppressor Proteins Ubiquitin Up-Regulation Vinculin Work Wound Healing Xenograft procedure antitumor effect cancer cell cell motility driving force in vivo insight loss of function malignant breast neoplasm migration mouse model overexpression protein inhibitor of activated STAT 1 research study rho GTP-Binding Proteins small hairpin RNA tumor tumor progression tumorigenesis ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Aberrant cell signaling is the main driving force in the development and progression of cancer. Protein inhibitor of activated STAT-1 (PIAS1) plays a fundamental role in cellular signaling by adding small ubiquitin like modifiers (SUMO-chains) onto target proteins. Our lab recently discovered that PIAS1 SUOMOylates the promyelocytic leukemia (PML) tumor suppressor. This event promotes the ubiquitin-mediated degradation of PML, aiding tumor survival. For example, PIAS1 depletion using shRNA in non-small cell lung cancer (NSCLC) and breast cancer cell lines leads to increased PML levels, followed susceptibility to apoptosis and impaired cell proliferation. In addition, my preliminary data show that PIAS1 overexpression in NIH3T3 and mouse embryonic fibroblasts (MEFs) reduces cell-to-cell contact inhibition. Furthermore, siRNA depletion of PIAS1 in cancer cells interferes with cell spreading and failure to migrate in wound healing assays. Notably, PIAS family members have recently been implicated in cytoskeleton dynamics. For instance, PIAS3 SUMOylation of the GTPase RAC1 increased lamelipodia formation in migrating cells. Moreover, PIAS1 SUMOylation of focal adhesion kinase (FAK) promoted increased cell viability under conditions of cellular stress. Together, these observations raise the hypothesis that PIAS1 may be implicated in tumor progression by potentiating tumor survival during cellular stress and in the promotion of cell migration by modulating cell shape, potentially through RAC/RHO and FAK proteins. This proposal aims to evaluate the impact of PIAS1 on the survival of cancer cells and their ability to metastasize using cellular and mouse models of lung cancer. This work is expected to provide a framework to understand how SUMOylation promotes tumorigenesis.

描述（由申请人提供）：异常细胞信号传导是癌症发展和发展的主要驱动力。活化STAT-1（PIAS1）的蛋白质抑制剂通过在靶蛋白上添加小的泛素（Sumo-Chains），在细胞信号传导中起着基本作用。我们的实验室最近发现，PIAS1 suomoyplain抑制了临床细胞性白血病（PML）肿瘤。该事件促进了泛素介导的PML的降解，这有助于肿瘤存活。例如，在非小细胞肺癌（NSCLC）和乳腺癌细胞系中使用shRNA的PIAS1耗竭会导致PML水平升高，随后对细胞凋亡的敏感性和细胞增殖受损。此外，我的初步数据表明，NIH3T3和小鼠胚胎成纤维细胞（MEFS）中的PIAS1过表达减少了细胞间接触抑制。此外，癌细胞中PIAS1的siRNA耗竭会干扰细胞在伤口愈合测定中扩散和未能迁移。值得注意的是，PIAS家族最近与细胞骨架动力学有关。例如，GTPase Rac1的PIAS3 Sumoylation增加了迁移细胞中的层层状形成。此外，在细胞应激条件下，局灶性粘附激酶（FAK）的PIAS1 Sumoylation促进了细胞活力的增加。总之，这些观察结果提出了以下假设：PIAS1可能通过在细胞应激期间增强肿瘤存活以及通过调节细胞形状来促进细胞迁移，这可能通过RAC/RHO和FAK蛋白来促进细胞迁移。该建议旨在评估PIAS1对癌细胞存活的影响及其使用肺癌细胞和小鼠模型转移的能力。预计这项工作将提供一个框架，以了解Sumoylation如何促进肿瘤发生。