UBR5's mechanisms of action in tumorigenesis and immunoregulation

临床分析表明，10-40%的病例中发生UBR 5基因扩增和过表达 许多主要类型的侵袭性人类癌症。此外，乳腺癌、卵巢癌和前列腺癌 携带UBR 5基因改变的癌症患者的生存率显著降低 与那些没有病变的人相比。我们的体外和体内实验工作首先 研究表明，UBR 5，像一个“癌基因”一样起着重要的作用， 乳腺癌和卵巢癌的生长和转移。我们还发现，肿瘤来源的UBR 5 通过细胞内源性和外源性驱动恶性三阴性乳腺肿瘤生长 它主要通过肿瘤细胞自主的方式促进转移。 因此，进一步阐明UBR 5的基础生物学和识别关键的信号传导结节 由UBR 5控制的有效致瘤和免疫调节活性不仅会促进 这不仅有助于科学，而且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当前的干预 战略布局 我们假设UBR 5通过不同的机制促进侵袭性BC/TNBC，包括 以E3泛素连接酶依赖性方式控制CDC 73蛋白周转， 增强干扰素-g诱导的PDL 1基因和E3连接酶中其他基因的转录- 独立的方式。我们建议拓宽和扩大对细胞的探索， 这些调制的分子机制在两个主要的具体目标。 (1)为了表征UBR 5作为一种免疫调节因子调节CDC 73蛋白的生化基础， E3泛素连接酶;并研究趋化因子CXCL 16在介导CDC 73 通过将细胞毒性T淋巴细胞募集到肿瘤部位来增强免疫刺激活性。 (2)为了研究UBR 5广泛增强细胞和分子机制， IFN-γ激活的信号通路独立于E3连接酶的活性，并探索 药理学UBR 5抑制的治疗潜力。 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UBR 5和/或其关键基因， 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.