UBR5's mechanisms of action in tumorigenesis and immunoregulation

临床分析表明，UBR5基因扩增和过度表达在10%-40%的病例中发生 在许多主要类型的侵袭性人类癌症中。此外，乳房、卵巢和前列腺 携带UBR5基因改变的癌症患者显著降低了存活率 与那些没有损伤的人相比。我们在体外和体内的实验工作第一次 证明了UBR5的功能就像一个癌基因，在促进 乳腺癌和卵巢癌的生长和转移。我们还表明，肿瘤来源的UBR5 通过细胞内源性和外源性驱动恶性三重负向乳腺肿瘤生长 机制，而它促进转移主要是通过肿瘤细胞自主的方式。 因此，进一步阐明UBR5‘S的基础生物学并鉴定关键信号结节 由UBR5控制的强大的致癌和免疫调节活动不仅将促进 这项科学不仅有助于开发高度恶性乳腺癌的新疗法 逃避内源性细胞控制机制并抵抗电流干预 战略。 我们假设UBR5通过不同的机制促进侵略性BC/TNBC，包括 以E3泛素连接酶依赖的方式控制CDC73蛋白的周转 增强干扰素-g诱导的E3连接酶中PDL1等基因的转录 以独立的方式。我们建议扩大和扩大对细胞和 这些调控的分子机制有两个主要的特定目的。 (1)研究UBR5对CDC73蛋白调控的生化基础 E3泛素连接酶；探讨趋化因子CXCL16在介导CDC73‘S中的作用 通过向肿瘤部位募集细胞毒性T淋巴细胞的免疫刺激活性。 (2)研究UBR5广泛增强的细胞和分子机制 干扰素-激活的不依赖E3连接酶活性的信号通路 药物抑制UBR5的治疗潜力。 这些研究的结果将为开发创新的治疗策略铺平道路。 通过靶向UBR5和/或其关键基因治疗高度侵袭性和耐药的乳腺癌 信号通路。

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.