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Structure, regulation, and biological functions of TIGAR and its role in diseases

Abstract

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.

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Fig. 1: TIGAR gene structure diagram, with different colors to mark different amino acid residue positions and unique structures, including the dPGM family characteristic motif RGH, catalytic domain, histidine phosphatase folding domain, and phosphate pocket.
Fig. 2: TIGAR is located in the cytoplasm and enters organelles, including the mitochondria, endoplasmic reticulum, and nucleus under different stress stimuli to regulate cell function.
Fig. 3: P53 family members, such as p53, p63, and p73, some transcription factors, such as SP1 and CREB, and noncoding miRNAs, such as miR-144, miR-885-5p, and miR-101 regulate the transcription of TIGAR.
Fig. 4: The enzymatic activity of TIGAR.
Fig. 5: TIGAR maintains cell homeostasis.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (81673421, 81973315 and 81730092), Natural Science Foundation of Jiangsu Higher Education (20KJA310008), Jiangsu Key Laboratory of Neuropsychiatric Diseases (BM2013003), and the Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD).

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Correspondence to Rui Sheng.

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Tang, J., Chen, L., Qin, Zh. et al. Structure, regulation, and biological functions of TIGAR and its role in diseases. Acta Pharmacol Sin 42, 1547–1555 (2021). https://doi.org/10.1038/s41401-020-00588-y

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Keywords

  • TIGAR
  • pentose phosphate pathway
  • NADPH
  • cerebral ischemia–reperfusion
  • neurological disorders
  • myocardial infarction
  • cancer

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