Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Neuropsychiatric Diseases, College of Pharmaceutical Sciences of Soochow University, Suzhou, 215123, China.
Acta Pharmacol Sin. 2021 Oct;42(10):1547-1555. doi: 10.1038/s41401-020-00588-y. Epub 2021 Jan 28.
TIGAR (TP53-induced glycolysis and apoptosis regulator) is the downstream target gene of p53, contains a functional sequence similar to 6-phosphofructose kinase/fructose-2, 6-bisphosphatase (PFKFB) bisphosphatase domain. TIGAR is mainly located in the cytoplasm; in response to stress, TIGAR is translocated to nucleus and organelles, including mitochondria and endoplasmic reticulum to regulate cell function. P53 family members (p53, p63, and p73), some transcription factors (SP1 and CREB), and noncoding miRNAs (miR-144, miR-885-5p, and miR-101) regulate the transcription of TIGAR. TIGAR mainly functions as fructose-2,6-bisphosphatase to hydrolyze fructose-1,6-diphosphate and fructose-2,6-diphosphate to inhibit glycolysis. TIGAR in turn facilitates pentose phosphate pathway flux to produce nicotinamide adenine dinucleotide phosphate (NADPH) and ribose, thereby promoting DNA repair, and reducing intracellular reactive oxygen species. TIGAR thus maintains energy metabolism balance, regulates autophagy and stem cell differentiation, and promotes cell survival. Meanwhile, TIGAR also has a nonenzymatic function and can interact with retinoblastoma protein, protein kinase B, nuclear factor-kappa B, hexokinase 2, and ATP5A1 to mediate cell cycle arrest, inflammatory response, and mitochondrial protection. TIGAR might be a potential target for the prevention and treatment of cardiovascular and neurological diseases, as well as cancers.
TIGAR（TP53 诱导的糖酵解和细胞凋亡调节因子）是 p53 的下游靶基因，包含与 6-磷酸果糖激酶/果糖-2,6-二磷酸酶（PFKFB）双磷酸酶结构域相似的功能序列。TIGAR 主要位于细胞质中；在应激反应下，TIGAR 易位到细胞核和细胞器，包括线粒体和内质网，以调节细胞功能。p53 家族成员（p53、p63 和 p73）、一些转录因子（SP1 和 CREB）和非编码 miRNA（miR-144、miR-885-5p 和 miR-101）调节 TIGAR 的转录。TIGAR 主要作为果糖-2,6-二磷酸酶，水解果糖-1,6-二磷酸和果糖-2,6-二磷酸，从而抑制糖酵解。反过来，TIGAR 促进磷酸戊糖途径通量，产生烟酰胺腺嘌呤二核苷酸磷酸（NADPH）和核糖，从而促进 DNA 修复，减少细胞内活性氧。因此，TIGAR 维持能量代谢平衡，调节自噬和干细胞分化，促进细胞存活。同时，TIGAR 还具有非酶功能，可以与视网膜母细胞瘤蛋白、蛋白激酶 B、核因子-κB、己糖激酶 2 和 ATP5A1 相互作用，介导细胞周期停滞、炎症反应和线粒体保护。TIGAR 可能是预防和治疗心血管和神经疾病以及癌症的潜在靶点。
