PML X亚型招募P62入核介导砷剂诱导PML-RARα融合蛋白降解的机制研究

砷剂是目前治疗急性早幼粒细胞白血病的有效药物之一，研究发现砷剂主要作用于PML-RARα融合蛋白的PML部分，诱导PML蛋白从可溶转变为不可溶，继而经蛋白酶体途径降解，最终达到治疗目的。目前砷剂治疗APL存在一定的瓶颈，但是具体原因尚不明确。本课题组研究发现，PML的七种亚型中PML X具有更灵敏的砷剂反应性，并且只有PML X亚型可以招募P62蛋白入核并与其共定位，进一步研究发现PML X亚型蛋白是连接P62与PML-RARα融合蛋白的关键蛋白并参与砷剂诱导的PML-RARα融合蛋白降解过程。本项目拟解决以下科学问题：1.揭示P62与PML X亚型相互作用关系，并明确PML X亚型招募P62入核参与PML-RARα降解的关键作用；2.阐明PML X蛋白介导砷剂调控PML-RARα降解的分子机制，明确PML X在砷剂治疗APL过程中重要意义，为临床治疗白血病提供新靶点及新思路。

Arsenic trioxide (As2O3) is one of the most effective therapeutic agents for patient with acute promyelocytic leukemia (APL). Recently, it has been found that As2O3 major targeted PML region of PML-RARα fusion protein, inducing PML transferred from soluble to insoluble, finally degraded by ubiquitin-proteasome depended pathway. However, the molecular mechanism is still unknown. In our preliminary experiment, we found that P62/SQSTM1 (autophagy-related specific protein) may mediate the nuclear shuttle of PML X isoforms . Besides, data has indicated that only PML X protein (but not other PML isoforms) could recruit and upregulate p62 protein expression. In addition, As2O3 has further enhanced p62 protein expression only in the presence of PML X isoform. Given these discovery, the interesting new results call into questions why p62 is involved in the process of PML transferred from soluble to insoluble. In this proposal, we are trying to answer the following issues; (A) How the PML protein isoform interacted with p62 proteins? (B) What is the molecular mechanism for the recruitment and induction of p62 by PML X protein? (C) What is the exact biological function of p62 for nuclear shuttling of PML X isoforms? Our results are expected to explain the exact mechanism of the process of PML transferred from soluble to insoluble and which will improve the life span of APL patients after treatment of arsenic in near future.