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CREB/ATF碱性亮氨酸拉链转录因子在代谢和细胞生长中的生物学功能

刘雨笑, 苏维彤, 李于^*

中国科学院上海营养与健康研究所，中国科学院营养代谢与食品安全重点实验室，中国科学院大学，上海 200031

摘要

营养过剩导致的糖脂代谢失调会引发机体胰岛素抵抗和代谢紊乱，并增加罹患多种癌症的风险。ATF/CREB家族新成员CREB/ATF碱性亮氨酸拉链转录因子(CREBZF)发挥连接代谢与细胞生长的作用。CREBZF通过与其它蛋白形成异源二聚体，行使其辅转录因子功能，调控基因表达。在高脂饮食诱导的小鼠胰岛素抵抗模型中，肝脏CREBZF缺失可减轻肝脏脂肪变性，此外，在肥胖小鼠与肝脏脂质沉积患者的肝脏中，CREBZF的表达水平显著上调。有趣的是，CREBZF还可通过与STAT3、p53和HCF-1等转录因子相互作用调控细胞增殖和凋亡。小鼠肝脏特异性敲除CREBZF促进细胞周期进程并增强增殖能力。本综述将重点论述CREBZF信号转导网络如何调控代谢与细胞生长，并探讨靶向CREBZF等分子作为治疗胰岛素抵抗、糖尿病、脂肪肝和癌症相关疾病的策略。

关键词： ATF/CREB蛋白家族; CREBZF; 糖脂代谢; 代谢性疾病; 细胞生长; 癌症

分类号：Q493.9;Q493.99;Q418

Biological functions of CREB/ATF bZIP transcription factor in metabolism and cell growth

LIU Yu-Xiao, SU Wei-Tong, LI Yu^*

CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China

Abstract

Nutrient overload-caused deregulation of glucose and lipid metabolism leads to insulin resistance and metabolic disorders, which increases the risk of several types of cancers. CREB/ATF bZIP transcription factor (CREBZF), a novel transcription factor of the ATF/CREB family, has emerged as a critical mechanism bridging the gap between metabolism and cell growth. CREBZF forms a heterodimer with other proteins and functions as a coregulator for gene expression. CREBZF deficiency in the liver attenuates hepatic steatosis in high fat diet-induced insulin-resistant mice, while the expression levels of CREBZF are increased in the livers of obese mice and humans with hepatic steatosis. Intriguingly, CREBZF also regulates cell proliferation and apoptosis via interaction with several transcription factors including STAT3, p53 and HCF-1. Knockout of CREBZF in hepatocytes results in enhanced cell cycle progression and proliferation capacity in mice. Here we highlight how the CREBZF signaling network contributes to the deregulation of metabolism and cell growth, and discuss the potential of targeting these molecules for the treatment of insulin resistance, diabetes, fatty liver disease and cancer.

Key words: ATF/CREB family; CREBZF; glucose and lipid metabolism; metabolic disease; cell growth; cancer

收稿日期：2020-12-15　　录用日期：2021-04-28

通讯作者：李于　　E-mail: liyu@sibs.ac.cn

DOI: 10.13294/j.aps.2021.0071

引用本文：

刘雨笑, 苏维彤, 李于. CREB/ATF碱性亮氨酸拉链转录因子在代谢和细胞生长中的生物学功能[J]. 生理学报 2021; 73 (5): 761-771.

LIU Yu-Xiao, SU Wei-Tong, LI Yu. Biological functions of CREB/ATF bZIP transcription factor in metabolism and cell growth. Acta Physiol Sin 2021; 73 (5): 761-771 (in Chinese with English abstract).