抑癌基因p53诱发CHARGE综合症的分子机制

报道：来自斯坦福大学医学院和密歇根大学医学院的研究人员首次将p53和CHARGE综合症的发病关联起来，该研究暗示了阐明CHARGE综合症发病的分子机制或有利于开发针对该疾病的靶向疗法，这篇文章刊登在2014年8月3日的《Nature》杂志上。

【题目】发育过程中p53异常活化引发机体出现CHARGE综合症的症状

【译文】CHARGE综合症是一种多方面异常的疾病，最常见的一些症状有眼缺损、心脏缺陷、后鼻孔闭锁、生长发育迟缓、泌尿生殖器发育不全和耳畸形。尽管70-90%CHARGE综合症的病例是由于CHD7基因（编码ATP依赖的染色质重组子的基因）的突变造成的，但是不同表型的发病机制仍不清楚。我们在小鼠体内敲入一个稳定的转录致死的肿瘤抑制蛋白p53的变种p5325,26,53,54和一个野生型p53等位基因（也被称为Trp53），奇怪的是，小鼠体内出现了晚期妊娠胚胎死亡，并伴随CHARGE综合症的一些表型，如眼缺损、内膜和外膜耳畸形、心脏流出道缺陷和颅面缺陷。我们发现p5325,26,53,54突变蛋白使野生型p53稳定并过度活化，诱导靶基因异常表达，进而导致发育过程中细胞周期停滞或细胞凋亡。重要的是，这些表型只在野生型p53等位基因中观察到，而asp5325,26,53,54/−胚胎是完全可以成活的。不仅如此，我们还发现CHD7可以结合到p53启动子上，从而负调控p53表达。小鼠的神经嵴细胞或患有CHARGE综合征的病人样本中CHD7缺失会导致p53活化。更吸引人的是，我们发现p53杂合子部分挽救了Chd7敲除的小鼠胚胎，这表明p53导致CHARGE综合症是由于CHD7的缺失。因此，发育过程中p53异常活化会促进CHARGE表型的发生，阐释了p53在发育综合症中发挥重要的作用，为CHARGE综合症的发病机制提供了重要的见解。

英文原稿

[Title] Inappropriate p53 activation during development induces features of CHARGE syndrome

[author] Jeanine L. Van Nostrand, Colleen A. Brady, Heiyoun Jung, Daniel R. Fuentes, Margaret M. Kozak, Thomas M. Johnson, 

             Chieh-Yu Lin, Chien-Jung Lin, Donald L. Swiderski, Hannes Vogel, Jonathan A. Bernstein, Tania Attié-Bitach, Ching-Pin 

             Chang, Joanna Wysocka, Donna M. Martin & Laura D. Attardi

 [Abstract] CHARGE syndrome is a multiple anomaly disorder in which patients present with a variety of phenotypes, including ocular 

                 coloboma, heart defects, choanal atresia, retarded growth and development, genitourinary hypoplasia and ear abnormalities. 

                 Despite 70–90% of CHARGE syndrome cases resulting from mutations in the gene CHD7, which encodes an ATP-dependent 

                 chromatin remodeller, the pathways underlying the diverse phenotypes remain poorly understood. Surprisingly, our studies 

                 of a knock-in mutant mouse strain that expresses a stabilized and transcriptionally dead variant of the tumour-suppressor 

                 protein p53 (p5325,26,53,54), along with a wild-type allele of p53 (also known as Trp53), revealed late-gestational embryonic 

                 lethality associated with a host of phenotypes that are characteristic of CHARGE syndrome, including coloboma, inner and outer 

                 ear malformations, heart outflow tract defects and craniofacial defects. We found that the p5325,26,53,54 mutant protein 

                 stabilized and hyperactivated wild-type p53, which then inappropriately induced its target genes and triggered cell-cycle arrest 

                 or apoptosis during development. Importantly, these phenotypes were only observed with a wild-type p53 allele, 

                 asp5325,26,53,54/− embryos were fully viable. Furthermore, we found that CHD7 can bind to the p53promoter, thereby 

                 negatively regulating p53 expression, and that CHD7 loss in mouse neural crest cells or samples from patients with CHARGE 

                 syndrome results in p53 activation. Strikingly, we found that p53 heterozygosity partially rescued the phenotypes in Chd7-null 

                 mouse embryos, demonstrating that p53 contributes to the phenotypes that result from CHD7 loss. Thus, inappropriate p53 

                 activation during development can promote CHARGE phenotypes, supporting the idea that p53 has a critical role in 

                 developmental syndromes and providing important insight into the mechanisms underlying CHARGE syndrome.

原文地址 

http://www.nature.com/nature/journal/vaop/ncurrent/full/nature13585.html