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K-Ras sumoylation in cell proliferation and transformation

细胞增殖和转化中的 K-Ras 修饰

基本信息

批准号：
9924462
负责人：
Yuan Chen
金额：
$ 49.75万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-15 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9924462
关键词：
Acetylation Animal Model Antineoplastic Agents Autophagocytosis Biochemical Biological Models Cell Proliferation Cell Survival Cell physiology Cells Development Ectopic Expression Enzymes Excision Family Glycine Growth Guanosine Triphosphate Phosphohydrolases In Vitro KRAS2 gene Lead Lysine MAP3K1 gene MEKs Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Mammalian Cell Mediating Methylation Modification Molecular Monomeric GTP-Binding Proteins Monoubiquitination Mutation Oncogenic Pancreas Patients Phosphorylation Post-Translational Protein Processing Process Proteins RAS genes Regulatory Pathway Research Resistance Role Series Signal Transduction Sumoylation Pathway System Testing Tumor-Derived Ubiquitin Ubiquitination Xenograft procedure anti-cancer base cancer therapy cell growth cell immortalization cell motility cell transformation design farnesylation gene product in vivo inhibitor/antagonist insight interest isopeptidase migration mouse model mutant novel palmitoylation pancreatic cancer cells pre-clinical protein protein interaction ral Guanine Nucleotide Exchange Factor ras GTPase-Activating Proteins ras Proteins small molecule inhibitor sulfoenolpyruvate targeted treatment therapeutic development therapy development tumor xenograft tumorigenesis ubiquitin-protein ligase

项目摘要

ABSTRACT Ras proteins are GTPases that activate multiple signaling cascades, which modulate cell survival, proliferation, migration, and differentiation. Ras proteins are regulated by almost all known post-translational modifications, including farnesylation, palmitoylation, phosphorylation, ubiquitination, and acetylation. However, it remains unknown whether Ras proteins are modified by sumoylation. We recently discovered that all three forms of Ras protein are SUMO3-modified. Our further studies reveal that lysine 42 (K42) is the primary residue for sumoylation, whereas PIASγ and MEKK1 are candidate E3 ligases that sumoylate Ras. Sumoylation is essential for activating K-Ras and its downstream signaling. Furthermore, we have discovered a series of SUMO E1 inhibitors that target SUMO conjugation both in vitro and in vivo. The lead compounds 27A and SB-264 potently inhibit sumoylation, but not ubiquitination or neddylation. Significantly, these compounds display excellent bioactivities toward killing transformed pancreatic cells with K-Ras mutations at glycine 12 or glycine 13 and suppress their migration. Given the role of sumoylation in controlling functions of key cellular regulators and the paramount importance of K- Ras in cell proliferation and transformation, we hypothesize that sumoylation promotes K-Ras activity and that the SUMO regulatory pathway is an excellent target for development of anti- cancer drugs. Three Specific Aims are proposed to test the validity of the hypothesis. We will determine the mechanism by which sumoylation regulates K-Ras activation, elucidate the regulatory network that controls K-Ras sumoylation, and investigate the efficacy of SUMO E1 inhibitors in suppressing proliferation of pancreatic cancer growth in preclinical mouse models. Further characterization of K-Ras sumoylation promises to have a profound impact on our understanding of the fundamental cellular signaling mechanisms that regulate cell growth. Given the discovery of novel SUMO E1 inhibitors, our proposed studies will help to accelerate the development of therapeutic applications that target ubiquitin-like modifications. !

摘要