UBR5's mechanisms of action in tumorigenesis and immunoregulation

UBR5在肿瘤发生和免疫调节中的作用机制

• 批准号: 10659844
• 负责人: XIAOJING MA
• 金额: $ 65.52万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659844
• 关键词: BRCA1 Mutation; Binding; Biochemical; Biology; C-terminal; CD8-Positive T-Lymphocytes; CTLA4 gene; Cancer Patient; Cartoons; Cells; Characteristics; Chimera organism; Chromatin; Cisplatin; Clinical; Combination immunotherapy; Complex; Cytotoxic T-Lymphocytes; DNA Sequence Alteration; Data; Development; Gene Amplification; Gene Expression Profile; Genes; Genetic Transcription; Genetically Engineered Mouse; Growth; Human; IRF1 gene; Immune checkpoint inhibitor; Immunosuppression; In Vitro; Interferons; Intervention; Lesion; Macrophage; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Mammary Neoplasms; Mediating; Modeling; Molecular; Mutation; Neoplasm Metastasis; Nodule; Oncogenes; Outcome Study; PRKR gene; Pathway interactions; Play; Poly A; Polyadenylation; Polyubiquitination; Property; Proteins; Proto-Oncogenes; RNA Polymerase II; Regulation; Role; STAT1 gene; Science; Signal Induction; Signal Pathway; Signal Transduction; Site; Structure-Activity Relationship; Testing; Therapeutic; Therapeutic Intervention; Time; Transcriptional Regulation; Tumor Escape; Tumor Suppressor Proteins; Tumor-Derived; Validation; Work; cancer cell; chemokine; chemotherapy; docetaxel; experimental study; genome-wide; immune checkpoint; immunoregulation; in vivo; innovation; malignant breast neoplasm; mammary epithelium; multicatalytic endopeptidase complex; neoplastic cell; novel; novel therapeutics; overexpression; pharmacologic; posttranscriptional; programmed cell death ligand 1; programmed cell death protein 1; programs; protein degradation; prototype; recruit; therapy resistant; transcription factor; transcriptome sequencing; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumorigenesis; tumorigenic; ubiquitin-protein ligase

Clinical analyses show that UBR5 gene amplifications and overexpression occur in 10-40% cases of many major types of aggressive human cancers. Furthermore, breast, ovarian and prostate cancer patients carrying genetic alterations in UBR5 have significantly reduced survivals compared to those without the lesions. Our experimental work in vitro and in vivo has first demonstrated that UBR5, functioning like an “oncogene”, plays a profound role in promoting breast and ovarian cancer growth and metastasis. We have also shown that tumor-derived UBR5 drives malignant triple negative mammary tumor growth through both cell-intrinsic and extrinsic mechanisms, whereas it facilitates metastasis primarily in a tumor cell-autonomous manner. Thus, further elucidating UBR5’s fundamental biology and identifying critical signaling nodules controlled by UBR5 in its potent tumorigenic and immunoregulatory activities will not only advance the science but also help the development of novel therapies for highly malignant breast cancer that evades the endogenous cellular control mechanisms and resist current interventional strategies. We hypothesize that UBR5 promotes aggressive BC/TNBC via distinct mechanisms that include controlling the CDC73 protein turnover in an E3 ubiquitin ligase-dependent manner and enhancing Interferon-g-induced transcription of the PDL1 gene and others in an E3 ligase- independent manner. We propose to broaden and expand the exploration of the cellular and molecular mechanisms of these modulations in two major specific aims. (1) To characterize the biochemical basis of CDC73 protein regulation by UBR5 acting as an E3 ubiquitin ligase; and investigate the role of the chemokine CXCL16 in mediating CDC73’s immunostimulatory activities via recruitment of cytotoxic T lymphocytes to the tumor site. (2) To investigate the cellular and molecular mechanism whereby UBR5 broadly enhances the IFN--activated signaling pathway independently of the E3 ligase activity and explore the therapeutic potential of pharmacological UBR5 inhibition. The outcome of these studies will pave the way for developing innovative therapeutic strategies for highly aggressive and therapy-resistant breast cancer by targeting UBR5 and/or its crucial signaling pathways.

临床分析表明，在10-40％的情况下，UBR5基因扩增和过表达发生 在许多主要类型的侵略性人类癌症中。此外，乳房，卵巢和前列腺 在UBR5中携带遗传改变的癌症患者的存活率显着降低 与没有病变的那些相比。我们在体外和体内的实验工作首先 证明UBR5像“癌基因”一样起作用，在促进中起着强烈的作用 乳腺癌和卵巢癌的生长和转移。我们还表明了肿瘤衍生的UBR5 通过细胞中的和外在的驱动恶性三重阴性乳腺肿瘤生长 机制，而它主要以肿瘤细胞自治方式托管转移。 这进一步阐明了UBR5的基本生物学并确定关键信号结节 由UBR5在其有效的结核菌和免疫调节活动中控制不仅会推进 科学，但也有助于开发高度恶性乳腺癌的新疗法 这逃避了内源性细胞控制机制并抵抗电流介入 策略。 我们假设UBR5通过包括 以E3的泛素连接酶依赖性方式控制Cdc73蛋白更新和 增强了E3连接酶中PDL1基因和其他的干扰素G诱导的转录 独立的方式。我们建议扩大和扩大细胞和细胞的探索 这些调制的分子机制在两个主要特定目的中。 （1）表征由UBR5充当CDC73蛋白调节的生化基础 E3泛素连接酶；并研究趋化因子CXCL16在介导Cdc73中的作用 通过将细胞毒性T淋巴细胞募集到肿瘤部位的免疫刺激活性。 （2）研究细胞和分子机制，从而大致增强了UBR5 IFN-激活的信号传导途径独立于E3连接酶活性并探索 药物UBR5抑制的治疗潜力。 这些研究的结果将为制定创新的治疗策略铺平道路 通过靶向UBR5和/或至关重要的高度侵略性和耐药性乳腺癌 信号通路。