第二軍醫(yī)大學基礎部章衛(wèi)平教授研究組的最新研究結果,，揭示了自主發(fā)現的鋅指蛋白ZBTB20是調控甲胎蛋白基因表達的關鍵分子。這一發(fā)現將刊登在8月5日正式出版的新一期國際著名學術期刊美國《國家科學院院刊》（PNAS）上,。
甲胎蛋白作為肝癌臨床診斷最重要的生化指標，其表達調控的機制及其與肝細胞增殖之間的聯(lián)系是長期以來備受矚目的重要科學問題,。到目前為止,，有關肝細胞甲胎蛋白基因出生后快速轉錄抑制及其癌變時重新激活的機理仍是未解之謎。
章衛(wèi)平教授與第二軍醫(yī)大學免疫學研究所曹雪濤院士合作,，于1998年首先從人樹突狀細胞中自主克隆了新型鋅指蛋白ZBTB20,，并于2001年在國際上率先報道了初步研究結果。此后,，章衛(wèi)平課題組在國家自然基金委,、科技部863、973計劃等項目資助下,，與國外大學合作,，利用條件基因打靶技術，建立了肝細胞特異性ZBTB20基因缺陷的小鼠模型,，發(fā)現其成年肝細胞雖然處于靜息狀態(tài),，但其甲胎蛋白的表達幾乎接近胎肝水平，揭示了ZBTB20的體內生物學作用及其靶基因,，明確了ZBTB20作為新型轉錄抑制因子可以直接抑制甲胎蛋白基因的表達,，由此提出了哺乳動物出生后肝臟甲胎蛋白基因下調主要由于ZBTB20的表達上調及其發(fā)揮的轉錄抑制作用所致的學術觀點。
據曹雪濤院士介紹,，該研究將有助于深入認識基因發(fā)育調控的機制和肝癌的細胞與分子生物學特性,。他強調說，進一步深入,、拓展ZBTB20在肝臟疾病中的表達和功能調控規(guī)律及其與肝臟疾病發(fā)生,、發(fā)展關系的研究,，有望為肝臟疾病的診治研究帶來新思路。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
