第二军医大学基础部章卫平教授研究组的最新研究结果，揭示了自主发现的锌指蛋白ZBTB20是调控甲胎蛋白基因表达的关键分子。这一发现将刊登在8月5日正式出版的新一期国际著名学术期刊美国《国家科学院院刊》（PNAS）上。
甲胎蛋白作为肝癌临床诊断最重要的生化指标，其表达调控的机制及其与肝细胞增殖之间的联系是长期以来备受瞩目的重要科学问题。到目前为止，有关肝细胞甲胎蛋白基因出生后快速转录抑制及其癌变时重新激活的机理仍是未解之谜。
章卫平教授与第二军医大学免疫学研究所曹雪涛院士合作，于1998年首先从人树突状细胞中自主克隆了新型锌指蛋白ZBTB20，并于2001年在国际上率先报道了初步研究结果。此后，章卫平课题组在国家自然基金委、科技部863、973计划等项目资助下，与国外大学合作，利用条件基因打靶技术，建立了肝细胞特异性ZBTB20基因缺陷的小鼠模型，发现其成年肝细胞虽然处于静息状态，但其甲胎蛋白的表达几乎接近胎肝水平，揭示了ZBTB20的体内生物学作用及其靶基因，明确了ZBTB20作为新型转录抑制因子可以直接抑制甲胎蛋白基因的表达，由此提出了哺乳动物出生后肝脏甲胎蛋白基因下调主要由于ZBTB20的表达上调及其发挥的转录抑制作用所致的学术观点。
据曹雪涛院士介绍，该研究将有助于深入认识基因发育调控的机制和肝癌的细胞与分子生物学特性。他强调说，进一步深入、拓展ZBTB20在肝脏疾病中的表达和功能调控规律及其与肝脏疾病发生、发展关系的研究，有望为肝脏疾病的诊治研究带来新思路。（生物谷Bioon.com）
生物谷推荐原始出处：
PNAS，doi: 10.1073/pnas.0800647105，Xuetao Cao，Weiping J. Zhang
Zinc finger protein ZBTB20 is a key repressor of alpha-fetoprotein gene transcription in liver
Zhifang Xie*,†, Hai Zhang*, Wenwei Tsai‡, Ye Zhang*, Yu Du*, Jigen Zhong*, Claude Szpirer§, Minghua Zhu¶, Xuetao Cao‖, Michelle Craig Barton‡, Michael J. Grusby**, and Weiping J. Zhang*,††
Abstract
The alpha-fetoprotein (AFP) gene is highly activated in fetal liver but is dramatically repressed shortly after birth. The mechanisms that underlie AFP transcriptional repression in postpartum liver are not well understood. AFP enhancer, repressor region, and promoter are implicated to be involved in AFP postnatal repression, but the major transcriptional repressor remains undefined. We previously identified a zinc finger protein gene ZBTB20. To determine its physiological functions in vivo, we have generated hepatocyte-specific ZBTB20 knockout mice by the Cre/loxP approach and demonstrated here that ZBTB20 ablation in liver led to dramatic derepression of the AFP gene in entire liver throughout adult life, although the hepatocytes were normally under nonproliferating status. Furthermore, we found that ZBTB20 was a transcriptional repressor capable of specifically inhibiting AFP promoter-driven transcriptional activity. Liver chromatin immunoprecipitation and mobility shift assays showed that ZBTB20 bound to AFP promoter directly. ZBTB20 was developmentally activated in liver after birth and inversely correlated with its AFP gene expression, suggesting that activated ZBTB20 expression in liver mediated AFP gene repression. Our data point to ZBTB20 as a key regulator governing AFP gene transcription and postulate a new model for the postnatal gene repression of AFP in liver.
