Department of Anus and Intestine Surgery, Department of Cardiology, and Department of Respiratory and Critical Care Medicine, The First Hospital of China Medical University, Shenyang 110001, China.
Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.
Pharmacol Res. 2024 Oct;208:107355. doi: 10.1016/j.phrs.2024.107355. Epub 2024 Aug 22.
The activating transcription factor (ATF)/ cAMP-response element binding protein (CREB) family represents a large group of basic zone leucine zip (bZIP) transcription factors (TFs) with a variety of physiological functions, such as endoplasmic reticulum (ER) stress, amino acid stress, heat stress, oxidative stress, integrated stress response (ISR) and thus inducing cell survival or apoptosis. Interestingly, ATF family has been increasingly implicated in autophagy and ferroptosis in recent years. Thus, the ATF family is important for homeostasis and its dysregulation may promote disease progression including cancer. Current therapeutic approaches to modulate the ATF family include direct modulators, upstream modulators, post-translational modifications (PTMs) modulators. This review summarizes the structural domain and the PTMs feature of the ATF/CREB family and comprehensively explores the molecular regulatory mechanisms. On this basis, their pathways affecting proliferation, metastasis, and drug resistance in various types of cancer cells are sorted out and discussed. We then systematically summarize the status of the therapeutic applications of existing ATF family modulators and finally look forward to the future prospect of clinical applications in the treatment of tumors by modulating the ATF family.
激活转录因子（ATF）/环腺苷酸反应元件结合蛋白（CREB）家族是一大类碱性亮氨酸拉链（bZIP）转录因子（TFs），具有多种生理功能，如内质网（ER）应激、氨基酸应激、热应激、氧化应激、综合应激反应（ISR），从而诱导细胞存活或凋亡。有趣的是，近年来 ATF 家族在自噬和铁死亡中的作用越来越受到关注。因此，ATF 家族对于维持体内平衡非常重要，其失调可能会促进疾病的进展，包括癌症。目前调节 ATF 家族的治疗方法包括直接调节剂、上游调节剂、翻译后修饰（PTM）调节剂。本综述总结了 ATF/CREB 家族的结构域和 PTM 特征，并全面探讨了其分子调控机制。在此基础上，梳理和讨论了它们在各种类型癌细胞中的增殖、转移和耐药性的影响途径。然后我们系统地总结了现有的 ATF 家族调节剂的治疗应用现状，最后展望了通过调节 ATF 家族治疗肿瘤的临床应用的未来前景。
