铁代谢调节p53信号途径的分子机制及其生理病理意义

Iron excess is closely associated with tumorigenesis in multiple types of human cancers and promote microbe infection,with underlying mechanisms yet unclear. Recently, iron deprivation has emerged as amajor strategy for chemotherapy, but it exerts tumor-suppression only onselect human malignancies. Here, we report that tumor suppressor p53 protein(p53) is downregulated during iron excess. Strikingly, heme, the iron polyporphyrin,binds to p53 protein, interferes with p53-DNA interactions and triggers nuclear export ofp53 followed by cytosolic degradation. Moreover, in a tumorigenicity assay, irondeprivation suppressed tumor growth largely with dependence on wild-type p53, suggesting thatupregulation of wild-type p53 signaling might critically underlie the selective efficacy ofiron deprivation. Our current findings thus identify the first direct link between iron/hemehomeostasis and the regulation of p53 signaling, which not only provides mechanisticinsights on tumorigenesis associated with iron excess, but may also help predict and improveoutcomes in iron-deprivation based chemotherapy. Here we propose to further investigate the structural basis and molecular mechanisms underlying the functional consequences of p53-heme interaction, through identifying E3 Ub ligase(s) implicated,crystographical analysis. Using the cell and animal model for iron excess, our research aim to mechanistically understand how iron excess might regulate tumor metabolism and promote microbe infection. Advance in this project would facilitate the development of better diagnostic and therapeutic means for related human disorders.

正常的铁代谢为一切生命体的生存繁衍所必须。肿瘤和神经退行性疾病、病原体感染等多种人类疾病的发生发展都与铁代谢异常有关。研究表明肿瘤铁代谢的异常调节肿瘤的增殖进化信号传导代谢及对药物的敏感性等；临床上也发现铁螯合等降低细胞内铁浓度的化疗方法对不同的肿瘤具有选择性的抑制作用，其机制未明。我们的研究表明铁代谢途径的重要产物血红素(Heme)可以特异性地与p53蛋白结合并促进其出核转运过程和细胞质中也发现铁螯合通过降低细胞内血红素的丰度稳定p53导致细胞周期阻滞从而抑制肿瘤增殖。本项目计划通过结构生物学研究和鉴定特异性地作用的泛素链接酶等深入探讨结合血红素后p53及其生物学效应的结构基础和分子机制；并在铁代谢异常的细胞和小鼠模型中，研究与p53-血红素结合后续相关的对其他代谢途径可能的调节作用，探讨铁代谢上调对肿瘤迁移、病原体感染等促进作用的病理机制，努力为相关疾病的诊治提供新的靶标和理论指导。

正常的铁代谢为一切生命体的生存繁衍所必须。肿瘤和神经退行性疾病、病原体感染等多种人类疾病的发生发展都与铁代谢异常有关。利用建立的p53基因敲除的高铁小鼠模型，分离得到p53-/-Hfe-/-小鼠成纤维细胞，对比p53+/+Hfe-/-和p53+/+Hfe+/+两种基因型细胞，发现铁对细胞代谢生长和凋亡的调控具有明显差异。初步分析铁代谢对肝脏原发性肿瘤HCC有一定的影响。.通过RNA干扰和CRISPR技术， 我们鉴定出p53蛋白的一个新E3泛素连接酶RING1，并通过研究发现，RING1通过直接跟p53蛋白相互作用并对其进行泛素化降解，从而调控p53蛋白介导的细胞生长和凋亡过程。我们也进一步在动物模型和病人样本中，揭示了这个调控通路在原发性肝癌HCC中的分子机制。