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Functions of a novel suppressor of oncogenic Ras

一种新型致癌 Ras 抑制剂的功能

基本信息

批准号：
10579551
负责人：
WILLIS X LI
金额：
$ 7.9万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10579551
关键词：
Attention Binding Binding Sites Biogenesis Cell Aging Cell Proliferation Chromatin Chromatin Structure Development Drosophila genus Epigenetic Process Event Future Gene Expression Gene Expression Regulation Gene Silencing Genetic Genetic Transcription Genomic DNA Genomics Goals Growth Heterochromatin Histone H3 Histones Homologous Gene Human Hypermethylation Inhibition of Cell Proliferation Investigation Knowledge Lysine Malignant Neoplasms Mediating Methods Methylation Mitosis Molecular Mutation Oncogenic Oncoproteins Organ Organ Size Organism Output Pathway interactions Play Proliferating Proteins RAS inhibition RNA Interference Regulation Reporting Research Resistance Role Sequence Homology Signal Transduction Small RNA System Therapeutic Tumor Suppression Tumor Suppressor Genes Tumor Suppressor Proteins Untranslated RNA chromatin modification epigenetic regulation fly histone methyltransferase histone modification novel overexpression recruit response restraint tumorigenesis

项目摘要

Functions of a novel suppressor of oncogenic Ras Oncogenic Ras accounts for more than 30% of all human cancers. Ras normally controls mitogenic pathways and functions as an on/off switch controlling cell proliferation. Heterochromatin appears to be a form of cellular restraint in both flies and humans that oncogenic Ras has to overcome to induce cell proliferation. Many tumor suppressors, such as Rb and BRCAs, play a role in heterochromatin formation, and an inability to form heterochromatin formation itself permits tumorigenesis in response to oncogenic Ras. However, how heterochromatin formation counteracts oncogenic Ras and how Ras can overcome heterochromatin-mediated tumor suppression remain unclear. Understanding how heterochromatin counteracts oncogenic signals and how oncogenic pathways overcome heterochromatin to induce growth and proliferation may lead to novel epigenetic cancer therapeutics. To investigate the connection from oncogenic mutations to epigenetic alterations, we have used Drosophila genetics to identify new players mediating cellular responses to oncogenic Ras, with a particular attention to nonconventional Ras signaling components. Among the novel suppressors of oncogenic Ras, we found that CRIF regulates both cell proliferation and heterochromatin formation. The objective of this project is to understand the mechanism by which the putative tumor suppressor CRIF antagonizes the effects of oncogenic Ras on cell proliferation. The long-term goal of the research is to elucidate how heterochromatin formation functions in epigenetic tumor suppression and how oncoproteins reorganize chromatin to induce cell proliferation and tumorigenesis. We hypothesize that CRIF counteracts oncogenic Ras by inhibiting cell proliferation and increasing heterochromatin formation, an epigenetic tumor suppression system. In this proposal, we plan to elucidate the molecular functions CRIF in counteracting oncogenic Ras-induced proliferation and in heterochromatin regulation. Specifically, we will investigate how CRIF resist oncogenic Ras in controlling proliferation, and the role of CRIF in regulating heterochromatin. Results from these studies will break new grounds for investigating the molecular mechanisms underlying the epigenetic effects of oncogenic Ras, the role of epigenetic dysregulation in cancer development, and the role heterochromatin in tumor suppression.

一种新的致癌RAS抑制因子的功能致癌RAS占所有人类癌症的30%以上。RAS通常控制有丝分裂途径并且起到控制细胞增殖的开/关开关的作用。异染色质似乎是细胞的一种形式在果蝇和人类中，致癌的RAS必须克服的限制才能诱导细胞增殖。许多肿瘤抑制子，如RB和BRCA，在异染色质的形成和不能形成中起作用异染色质的形成本身允许肿瘤的形成响应致癌的RAS。然而，如何异染色质的形成抵消致癌RAS以及RAS如何克服异染色质介导的肿瘤抑制仍不清楚。了解异染色质如何中和致癌信号和致癌途径如何克服异染色质诱导生长和增殖可能导致新的表观遗传癌症疗法。为了研究致癌突变与表观遗传学改变之间的联系，我们用果蝇遗传学以确定介导细胞对致癌RAS反应的新角色，并特别关注非常规RAS信令组件。在致癌RAS的新抑制因子中，我们发现 CRIF调节细胞的增殖和异染色质的形成。这个项目的目标是了解可能的肿瘤抑制因子CRIF拮抗致癌作用的机制 RAS对细胞增殖的影响。这项研究的长期目标是阐明异染色质是如何形成的表观遗传肿瘤抑制中的作用以及癌蛋白如何重组染色质诱导细胞增殖和肿瘤发生。我们假设CRIF通过抑制细胞来对抗致癌的RAS 增殖并增加异染色质的形成，这是一种表观遗传的肿瘤抑制系统。在这建议，我们计划阐明CRIF在对抗致癌RAS诱导的分子功能增殖和异染色质调节。具体地说，我们将研究CRIF如何抵抗致癌的RAS 在控制增殖方面，以及CRIF在调节异染色质中的作用。这些研究的结果将为研究致癌的表观遗传效应的分子机制开辟了新的基础 RAS，表观遗传失调在肿瘤发展中的作用，以及异染色质在肿瘤中的作用压制。