REGgamma蛋白酶体功能的调控机制

Ubiquitin-independent, proteasome mediated protein degradation is a developing research field with great application potential. The proteasome activator REGgamma is a well-known representative in the ubiquitin-independent proteasome activator family, mediating physiological and pathological processes such as reproduction, metabolism, and tumor development. It remains unknown how upstream signals quickly and dynamically regulate the activity of REGgamma-proteasome via coupled posttranslational modification of regulatory factors with substrate protein degradation. Our initial screen with different methods identified a novel REGgamma interacting protein called NIP30. Phosphorylated NIP30 can bind REGgamma and prevent degradation of substrate protein p21, a tumor suppressor. Cell cycle regulator CDC25A was found to dephosphorylate NIP30 and dynamically modulate REGgamma-dependent degradation of p21 during G1-S phase in cell cycle. To elucidate the mechanisms regulating the CDC25A-NIP30-REGgamma-p21 pathway, we will dissect this pathway at molecular, cellular, protein structural and animal model levels. Given that CDC25A will be degraded upon DNA damage, we will integrate clinical tumor sample studies to address signal networks involved in regulation of posttranslational modification and protein degradation in the above pathway. Successful accomplishment of the proposed work will be of high impact on personalized therapy and development of novel small molecules against malignant tumors.

蛋白酶体介导的非泛素依赖型蛋白质降解是一个正在兴起,前景广阔的研究领域。REGgamma（REG）是非泛素依赖型蛋白质降解的代表性激活因子，调节生殖发育、代谢、肿瘤等生理病理过程。上游信号如何通过蛋白质修饰快速、动态调控REG-蛋白酶体活性仍然不明了。我们用不同方法都筛选到一个全新的REG结合蛋白NIP30。磷酸化NIP30紧密结合REG，阻止REG-蛋白酶体对底物p21的降解。细胞周期因子CDC25A去磷酸化酶在G1-S期对该过程具有动态调控，影响肿瘤抑制因子p21的降解。为阐明这一偶联蛋白质修饰与降解的信号传导调控机制，我们将从分子、细胞、蛋白结构、模式动物层面研究CDC25A-NIP30-REG-p21通路的重要意义；基于CDC25A在DNA损伤时降解，还将研究肿瘤样本中CDC25A对REG-蛋白酶体的调控。完成这些研究能为恶性肿瘤个性化治疗以及相关疾病的新药开发提供重要的理论基础。

蛋白酶体介导的非泛素依赖型蛋白质降解是一个正在兴起,前景广阔的研究领域。REGgamma（REGγ）是非泛素依赖型蛋白质降解的代表性激活因子，调节生殖发育、代谢、肿瘤等生理病理过程。上游信号如何通过蛋白质修饰快速、动态调控REG-蛋白酶体活性仍然不明了。我们用不同方法都筛选到一个全新的REGgamma结合蛋白NIP30。磷酸化NIP30紧密结合REGgamma，阻止REGgamma-蛋白酶体对底物p21的降解。细胞周期因子CDC25A去磷酸化酶在G1-S期对该过程具有动态调控，影响肿瘤抑制因子p21的降解。为阐明这一偶联蛋白质修饰与降解的信号传导调控机制，我们将从分子、细胞、蛋白结构、模式动物层面研究CDC25A-NIP30-REGgamma-p21通路的重要意义；基于CDC25A在DNA损伤时降解，我们研究了肿瘤样本中CDC25A对REGgamma-蛋白酶体的调控。完成这些研究能为恶性肿瘤个性化治疗以及相关疾病的新药开发提供重要的理论基础