26S蛋白酶体调控几乎所有的细胞功能并与包括癌症在内的多种疾病密切相关。作为真核细胞内负责蛋白质降解的主要细胞器，蛋白酶体自身在生理病理过程中如何被调控是目前亟待解决的重要科学问题。申请人此前报导了目前已知的唯一一个与26S蛋白酶体特异性结合的磷酸酶UBLCP1，揭示了可逆性磷酸化对蛋白酶体的重要调控作用。后续结果显示抑制UBLCP1的表达对癌细胞增殖、迁移、信号转导等有显著影响，提示UBLCP1可能成为新的药物靶标。本项目拟利用细胞生物学、生物化学、动物模型和癌症生物学的成熟实验体系，结合CRISPR基因编辑、磷酸化特异性抗体、全激酶组筛选、定量质谱、深度测序等先进工具方法，对UBLCP1调控蛋白酶体磷酸化的分子机制、细胞功能及其在肿瘤发生发展中的临床意义进行全面系统的研究。对这些问题的解答将加深我们对于蛋白酶体调控这一基本生物学问题的理解，并为针对蛋白酶体系统的抗癌疗法提供新的思路。

The 26S proteasome is the primary organelle for protein degradation in eukaryotic cells. It is required for almost every cellular function and is implicated in a variety of human diseases including cancer. However, how this “cellular trashcan” itself is regulated during pathophysiological processes is an important question that remains poorly understood. My earlier work identified the only proteasome-specific phosphatase known to date, UBLCP1, and demonstrated a key role of reversible phosphorylation in proteasome regulation. Subsequenct studies showed that downregulation of UBLCP1 has a significant impact on cancer cell proliferation, migration and signal transduction, suggesting the potential therapeutic value of targeting this proteasome phosphatase. In this proposal, we will systematically examine UBLCP1-mediated proteasome regulation at molecular and cellular levels as well as in the context of cancer formation and progression. To achieve this goal, established approaches of cell biology, biochemistry, mouse genetics and tumor biology will be employed in combination with state-of-the-art research tools such as gene editing with CRISPR/Cas9, phospho-specific antibodies, kinome screen, quantitative mass spectrometry and deep sequencing. Completion of this study will greatly improve our understanding of proteasome regulation as a fundamental question of biology, and will provide new possibilities for proteasome-oriented anti-cancer therapies.