PML小泛素相关修饰及其核体动态形成：心肌细胞凋亡干预的新靶标

Acute promyelocytic leukaemia protein (PML) is a key organizer of cellular nuclear substructures known as promyelocytic leukemia nuclear bodies (PML-NBs) and its function maintenance. However, the role and biofunction of PML has not been explored in major heart diseases. It is known that As2O3 (Arsenic Trioxide, ATO), as an effective drug for acute promyelocytic leukemia had exhibited myocardial toxicity, which is associated with induction of apoptosis in cardiaomyocytes. Moreover, a recent report in Science has revealed that As2O3 is able to directly bind to PML protein and promoted its modification by the small ubiquitin-like modifier family members (SUMOs) and leading to enhanced recruitment function of PML-NBs, which strongly suggests that PML is a new potential regulator for apoptosis in cardiomyocytes. Based on our previous studyon myocardial toxicity of As2O3, the present proposal aims to investigate the changing rule of SUMOylated PML and PML-NBs in cardiac ischemia mouse;to establish the molecular mechanisms by which PML regulates cardiomyocytes apoptosis, including the signaling of p53 and p73; to explore and compare the effects of administration of SUMOs inhibitor 2-D08 or silencing of RNF4 on PML SUMOylation in intervention of apoptosis process in cardiomyocytes. The present proposal will firstly explain the role of PML and associated PML-NBs in cardiac myocytes and provide a novel therapeutic target for major heart diseases.

PML为早幼粒细胞白血病蛋白，是维持细胞核亚结构PML核体（PML-NBs）结构及功能的关键分子，但其在重大心脏疾病中的功能尚未被揭示。已知治疗早幼粒细胞白血病药物三氧化二砷(As2O3)具有心肌毒性且与诱导心肌细胞凋亡相关。Science杂志报道PML为As2O3直接作用靶点，促其发生小泛素化修饰（SUMO）并导致PML-NBs募集功能增强，预示PML可能为心肌细胞凋亡的重要调控分子。本申请在对As2O3心肌毒性研究工作的基础上，首次揭示SUMO修饰PML及其PML-NBs在心肌梗死/心衰中的动态变化规律；建立SUMO修饰PML通过募集p53、p73进入PML-NBs调控心肌细胞凋亡的分子机制；探索给予SUMOs抑制剂2-D08或沉默RNF4是否可影响SUMO修饰PML过程，并对心肌细胞凋亡发挥重要调控作用。该研究首次探讨了PML在心肌细胞凋亡中的作用，并为重大心脏疾病提供新的干预靶标。

PML为早幼粒细胞白血病蛋白，是维持细胞核亚结构PML核体（PML-NBs）结构及功能的关键分子，但其在重大心脏疾病中的功能尚未被揭示。已知治疗早幼粒细胞白血病药物三氧化二砷(As2O3)具有心肌毒性且与诱导心肌细胞凋亡相关。Science杂志报道PML为As2O3直接作用靶点，促其发生小泛素化修饰（SUMO）并导致PML-NBs募集功能增强，预示PML可能为心肌细胞凋亡的重要调控分子。本项目首次揭示SUMO修饰PML及其 PML-NBs在心肌梗死/心衰中的动态变化规律；我们鉴定了缺血心脏和氧化应激诱导的凋亡心肌细胞RNF4的改变。我们利用腺相关病毒敲除动物体内RNF4后，促进了PML SUMO化修饰，进而促进了p53的募集和功能，从而促进心肌细胞凋亡，加剧了心肌缺血动物心肌重构，心功能进一步的恶化，充分证明PML/RNF4/p53在心肌缺血中的调控作用；本项目建立SUMO修饰PML通过募集p53进入PML-NBs 调控心肌细胞凋亡的分子机制；探索给予SUMOs抑制剂2-D08或沉默RNF4是否可影响SUMO修饰PML过程。该研究首次探讨了PML在心肌细胞凋亡中的作用 ，并为重大心脏疾病提供新的干预靶标。