Affinage

TIGAR

Fructose-2,6-bisphosphatase TIGAR · UniProt Q9NQ88

Length
270 aa
Mass
30.1 kDa
Annotated
2026-04-28
100 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TIGAR is a p53-inducible histidine phosphatase that functions as a metabolic regulator linking glycolysis suppression, antioxidant defense, and non-enzymatic signaling scaffolding. Its highest catalytic efficiency is toward 2,3-bisphosphoglycerate, though it also hydrolyzes fructose-2,6-bisphosphate, thereby diverting glucose flux from glycolysis into the pentose phosphate pathway to generate NADPH and ribose-5-phosphate for ROS scavenging and nucleotide synthesis (PMID:16839880, PMID:24423178, PMID:23726973). Under hypoxia, TIGAR translocates to mitochondria where it binds HK2 to enhance hexokinase activity and interacts with SDH-A to suppress succinate dehydrogenase activity and ferroptosis, while in the nucleus it acts as a phosphatase-independent co-factor that facilitates NRF2 chromatin recruitment and NRF2-target gene expression (PMID:23185017, PMID:38494143, PMID:35847493). Independent of its enzymatic activity, TIGAR also competes with NEMO for LUBAC binding to suppress NF-κB signaling and directly binds TAK1 in macrophages to promote inflammatory ubiquitination, establishing TIGAR as a dual metabolic enzyme and protein-interaction scaffold (PMID:29650758, PMID:38773142).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2006 High

    Identifying TIGAR as a p53 target with fructose-2,6-bisphosphatase activity established the first link between p53, glycolysis inhibition, and ROS-dependent cell survival.

    Evidence Microarray screen followed by overexpression/knockdown with ROS and apoptosis assays in human cancer cell lines

    PMID:16839880

    Open questions at the time
    • Enzymatic mechanism and true preferred substrate unresolved
    • Whether TIGAR functions independently of p53 unknown
  2. 2008 High

    Solving the crystal structure revealed a histidine phosphatase fold rather than a canonical bisphosphatase domain, redefining TIGAR's catalytic mechanism and evolutionary origin.

    Evidence X-ray crystallography of zebrafish TIGAR plus in vitro phosphatase assays with recombinant human protein

    PMID:19015259

    Open questions at the time
    • Preferred physiological substrate still unclear
    • No human structure available
  3. 2009 High

    Demonstrating that TIGAR suppresses autophagy via ROS reduction extended its role beyond apoptosis to a broader metabolic stress response.

    Evidence TIGAR knockdown/overexpression with autophagy markers and ROS measurement under nutrient starvation

    PMID:19713938

    Open questions at the time
    • Mechanism of autophagy suppression not fully delineated beyond ROS
    • Context-dependence of mTOR involvement unresolved
  4. 2011 Medium

    Mapping SP1 as essential for basal TIGAR transcription showed that TIGAR is constitutively expressed through p53-independent mechanisms, broadening the regulatory framework.

    Evidence Deletion reporter assays, EMSA, and ChIP for SP1 on the TIGAR promoter

    PMID:21761199

    Open questions at the time
    • Relative contributions of SP1 vs. p53 to TIGAR levels in different tissues unclear
    • No in vivo SP1 KO validation
  5. 2012 High

    Showing hypoxia-induced mitochondrial translocation and HK2 binding revealed a non-canonical, compartment-specific protective mechanism distinct from cytosolic bisphosphatase activity.

    Evidence Subcellular fractionation, reciprocal Co-IP of TIGAR–HK2, HIF-1α epistasis under hypoxia

    PMID:23185017

    Open questions at the time
    • Structural basis for TIGAR–HK2 interaction unknown
    • Whether mitochondrial TIGAR retains phosphatase activity in that compartment unclear
  6. 2013 High

    In vivo knockout studies established that TIGAR's PPP-promoting activity is required for intestinal regeneration, linking its metabolic function to tissue homeostasis through NADPH and nucleotide provision.

    Evidence TIGAR KO mice, intestinal organoids, xenograft models with ROS scavenger and nucleoside rescue

    PMID:23726973

    Open questions at the time
    • Whether TIGAR is required for regeneration in all tissues not tested
    • Relative importance of NADPH vs. ribose contribution unresolved
  7. 2014 High

    Identifying 2,3-bisphosphoglycerate as the kinetically preferred substrate (~400-fold over F-2,6-BP) fundamentally reframed TIGAR's primary enzymatic function.

    Evidence In vitro kinetics on recombinant human TIGAR across substrate panel, plus 2,3-BPG accumulation in TIGAR-depleted cells

    PMID:24423178

    Open questions at the time
    • Physiological consequence of 2,3-BPG regulation (e.g., hemoglobin oxygen affinity in erythrocytes) not explored
    • Relative in vivo contribution of 2,3-BPG vs. F-2,6-BP hydrolysis context-dependent
  8. 2015 High

    Genetic epistasis between TIGAR and RAC1 in APC-null intestinal cells revealed that TIGAR functions to limit damaging ROS while RAC1/NOX generates pro-proliferative ROS, establishing opposing ROS-regulatory roles in tumorigenesis.

    Evidence In vivo TIGAR KO × RAC1 KO × Myc KO in APC-deleted mouse intestine with organoid cultures

    PMID:26679840

    Open questions at the time
    • How TIGAR loss and RAC1 loss cooperate to suppress proliferation mechanistically unresolved
    • Applicability beyond intestinal tumors not tested
  9. 2015 Medium

    Demonstrating that basal and stress-induced TIGAR expression occurs independently of p53 and TAp73 in most mouse tissues resolved whether p53 is strictly required for TIGAR function.

    Evidence p53 KO and TAp73 KO mice with ionizing radiation stress and tissue-level protein analysis

    PMID:26247727

    Open questions at the time
    • Full set of p53-independent transcription factors driving TIGAR only partially mapped
    • Tissue-specific variation in regulatory dependencies not comprehensively tested
  10. 2018 High

    Discovery that TIGAR inhibits NF-κB by competing with NEMO for LUBAC binding — independent of phosphatase activity — established TIGAR as a non-enzymatic signaling scaffold.

    Evidence Reciprocal Co-IP, ubiquitination assays, phosphatase-dead mutant, TIGAR KO mice with adipose NF-κB readout

    PMID:29650758

    Open questions at the time
    • Structural basis of TIGAR–LUBAC interaction unknown
    • Whether this function operates in immune cells beyond adipocytes unclear at this time
  11. 2019 High

    Identifying ATP5A1 as a direct mitochondrial binding partner linked TIGAR to ATP synthase regulation and mitochondrial biogenesis via SIRT1–PGC1α, expanding its mitochondrial functions beyond HK2.

    Evidence GST pull-down/LC-MS, TIGAR KO mouse exercise model, mitochondria-targeted TIGAR overexpression

    PMID:30726106

    Open questions at the time
    • Whether TIGAR modulates ATP synthase catalytic mechanism or assembly unknown
    • Relevance beyond skeletal muscle not demonstrated
  12. 2020 High

    In a KRAS-driven PDAC model, TIGAR was shown to support tumor initiation by ROS limitation while its loss paradoxically promoted metastasis via MAPK activation, revealing stage-dependent roles in cancer.

    Evidence TIGAR KO in KRAS-driven PDAC mice, antioxidant rescue of metastatic phenotype, MAPK signaling analysis

    PMID:31983610

    Open questions at the time
    • Mechanism by which elevated ROS specifically activates MAPK over other pathways not defined
    • Generalizability to non-KRAS-driven cancers unclear
  13. 2021 Medium

    Identification of TRIM31 and subsequently TRIM35 as E3 ubiquitin ligases for TIGAR established that TIGAR protein turnover is governed by proteasomal degradation, with physiological relevance in ischemia-reperfusion injury.

    Evidence Co-IP, ubiquitination assays, proteasome inhibitor rescue, TRIM31 KO and TRIM35 KD in ischemia models

    PMID:34218200 PMID:35421414

    Open questions at the time
    • Whether TRIM31 and TRIM35 target overlapping or distinct TIGAR pools unknown
    • Ubiquitination sites on TIGAR not mapped
    • Each finding from a single lab
  14. 2021 Medium

    Showing that nuclear TIGAR directly recruits NRF2, MLL1, and elongating Pol-II to chromatin independently of enzymatic activity uncovered a transcriptional co-activator function.

    Evidence Co-IP (TIGAR–NRF2), ChIP for NRF2/MLL1/Pol-II, enzymatic-dead TIGAR mutant, gain/loss-of-function

    PMID:35847493

    Open questions at the time
    • How TIGAR reaches the nucleus and what triggers nuclear import unknown
    • Structural basis of TIGAR–NRF2 interaction not determined
    • Single-lab finding
  15. 2024 High

    Demonstrating that TIGAR binds TAK1 via residues 152–161 to promote TRAF6-mediated ubiquitination in macrophages revealed a pro-inflammatory scaffolding role, opposing its anti-NF-κB activity in other contexts.

    Evidence Reciprocal Co-IP, domain mapping/mutagenesis, myeloid-specific Tigar KO in LPS and CLP sepsis models

    PMID:38773142

    Open questions at the time
    • How TIGAR's opposing effects on NF-κB (LUBAC inhibition vs. TAK1 activation) are coordinated cell-type-specifically not resolved
    • Direct structural model of TIGAR–TAK1 complex lacking
  16. 2024 Medium

    Discovery that mitochondrial TIGAR directly binds SDH-A and modulates its acetylation/succinylation to suppress SDH activity and neuronal ferroptosis established a PPP-independent antioxidant mechanism.

    Evidence Co-IP (TIGAR–SDH-A), SDH activity assays, PTM analysis, enzymatic-dead TIGAR mutant, prolonged OGD and stroke models

    PMID:38494143

    Open questions at the time
    • Whether TIGAR directly catalyzes PTM changes on SDH-A or recruits acetyltransferases/deacetylases unknown
    • Single-lab finding requiring independent confirmation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TIGAR's enzymatic and non-enzymatic functions are spatiotemporally coordinated across subcellular compartments — and how cell-type-specific contexts determine whether TIGAR promotes or suppresses NF-κB signaling — remains unresolved.
  • No structural model of human TIGAR with any of its non-substrate partners (HK2, LUBAC, TAK1, NRF2, SDH-A, ATP5A1)
  • Signals controlling nuclear vs. mitochondrial vs. cytosolic distribution undefined
  • In vivo relevance of 2,3-BPG phosphatase activity in erythroid and non-erythroid tissues not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 3 GO:0060090 molecular adaptor activity 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005739 mitochondrion 4 GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-162582 Signal Transduction 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-9612973 Autophagy 2
Partners
ATP5A1HK2HOIPNRF2SDHATAK1TRIM31TRIM35

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 TIGAR is a p53-inducible gene that functions as a fructose-2,6-bisphosphatase, lowering fructose-2,6-bisphosphate levels in cells, thereby inhibiting glycolysis, reducing intracellular ROS, and protecting cells from ROS-associated apoptosis. Gene expression microarray identification followed by functional assays (ROS measurement, apoptosis assays, TIGAR knockdown/overexpression in cells) Cell High 16839880
2008 Crystal structure of zebrafish TIGAR reveals a histidine phosphatase fold with a catalytic histidine residue; recombinant human and zebrafish TIGAR hydrolyzes fructose-2,6-bisphosphate and fructose-1,6-bisphosphate but not fructose-6-phosphate in vitro; the active site is open and positively charged, most closely related to bacterial PhoE phosphatase and the bisphosphatase domain of bifunctional PFK2. X-ray crystallography and in vitro phosphatase assay with recombinant protein The Journal of biological chemistry High 19015259
2009 TIGAR modulates intracellular ROS in response to nutrient starvation or metabolic stress and functions to inhibit autophagy through ROS suppression, independent of the mTOR pathway and p53. TIGAR knockdown/overexpression with autophagy markers (LC3, Beclin-1), ROS measurement, nutrient deprivation assays The EMBO journal High 19713938
2012 Under hypoxia, a fraction of TIGAR protein relocalizes to mitochondria and forms a complex with hexokinase 2 (HK2), increasing HK2 activity; mitochondrial localization depends on mitochondrial HK2 and HIF-1α activity; the fructose-2,6-bisphosphatase activity of TIGAR is independent of HK2 binding and mitochondrial localization, but both activities contribute to limiting mitochondrial ROS and protecting from cell death. Subcellular fractionation, co-immunoprecipitation (TIGAR-HK2), HIF-1α inhibition, hypoxia treatment, cell death assays Proceedings of the National Academy of Sciences of the United States of America High 23185017
2013 TIGAR is required for intestinal regeneration in vivo and ex vivo; its fructose-2,6-bisphosphatase activity promotes the pentose phosphate pathway to produce NADPH for antioxidant function and ribose-5-phosphate for nucleotide synthesis; growth defects from TIGAR loss were rescued by ROS scavengers and nucleosides. TIGAR knockout mice, intestinal organoid cultures, xenograft tumor models, genetic rescue with ROS scavengers/nucleosides Developmental cell High 23726973
2014 TIGAR is identified as the phosphoglycolate-independent 2,3-bisphosphoglycerate (2,3-BPG) phosphatase; recombinant human TIGAR most efficiently hydrolyzes 2,3-BPG (~400-fold greater catalytic efficiency than for fructose-2,6-bisphosphate); loss of TIGAR leads to up to 5-fold increases in cellular 2,3-BPG levels. In vitro phosphatase assay with recombinant human TIGAR on panel of substrates; genetic and shRNA cell culture models measuring 2,3-BPG and F-2,6-BP levels The Biochemical journal High 24423178
2014 TIGAR mediates p21-independent, p53-dependent G1-phase arrest in cancer cells by suppressing CDK-2, CDK-4, CDK-6, Cyclin D, and Cyclin E, and promoting dephosphorylation of RB protein, stabilizing the RB-E2F1 complex and preventing S-phase entry. Co-immunoprecipitation (RB-E2F1), chromatin immunoprecipitation, luciferase reporter assays, western blot, cell cycle analysis, tumor xenograft model British journal of cancer Medium 22782351
2014 TIGAR protects ischemic brain via enhancing pentose phosphate pathway flux (increasing G6PD and NADPH production) and preserving mitochondrial function; TIGAR translocates to mitochondria during ischemia/reperfusion; supplementation of NADPH rescues the neuronal injury caused by TIGAR knockdown. Lentiviral TIGAR overexpression/knockdown in mice and neurons, in vivo stroke model (MCAO), subcellular fractionation, G6PD activity assay, ROS/GSH/caspase-3 measurements The Journal of neuroscience High 24872551
2015 TIGAR and RAC1 have opposing effects on ROS in intestinal cells following APC loss: TIGAR limits damaging ROS while RAC1-driven NOX generates pro-proliferative ROS; loss of TIGAR increases ROS damage and inhibits proliferation; despite opposing effects on ROS, loss of both TIGAR and RAC1 cooperates to suppress intestinal proliferation. 3D organoid cultures, in vivo mouse models (APC deletion), genetic epistasis (TIGAR KO × RAC1 KO × Myc KO), ROS measurements Genes & development High 26679840
2015 TIGAR regulates DNA damage response by relocating to the nucleus after genotoxic drug treatment or hypoxia; TIGAR controls phosphorylation of ATM through Cdk5, independent of the PPP pathway; knockdown of TIGAR exacerbated DNA damage, partly reversed by NADPH, ribose, or ROS scavenger NAC. Subcellular fractionation/imaging, siRNA knockdown, pharmacological Cdk5 inhibition, γH2AX foci assay, NADPH/ribose rescue experiments Scientific reports Medium 25928429
2018 TIGAR directly binds to and inhibits the linear ubiquitin assembly complex (LUBAC) by competing with NEMO for association with LUBAC, thereby preventing linear ubiquitination of NEMO, blocking IKKβ phosphorylation/activation, and suppressing NF-κB signaling; this function is independent of TIGAR phosphatase activity as a phosphatase-dead mutant retains NF-κB inhibitory activity. Co-immunoprecipitation, ubiquitination assays, phosphatase-dead TIGAR mutant, TIGAR knockout mice (adipose tissue NF-κB signaling), adipocyte-specific TIGAR overexpression The Journal of biological chemistry High 29650758
2019 TIGAR translocates to mitochondria in skeletal muscle during exhaustive exercise and binds directly to ATP synthase F1 subunit α (ATP5A1), increasing ATP generation, maintaining mitochondrial membrane potential, and reducing mitochondrial oxidative stress; TIGAR also regulates mitochondrial biogenesis through the SIRT1-PGC1α deacetylation pathway. GST-TIGAR pull-down followed by LC-MS (identifies ATP5A1), TIGAR KO mice exhaustive swimming test, mitochondrial fractionation, overexpression of mitochondria-targeted TIGAR, SIRT1 deacetylation assays FASEB journal High 30726106
2019 TIGAR promotes neural stem cell (NSC) differentiation by facilitating metabolic reprogramming from glycolysis to oxidative phosphorylation; TIGAR knockdown decreases acetyl-CoA levels and H3K9 acetylation at the promoters of neuronal differentiation genes (Ngn1, NeuroD1, Gfap); acetate supplementation (as acetyl-CoA precursor) rescues the differentiation defect caused by TIGAR knockdown. NSC culture, TIGAR knockdown/overexpression, acetyl-CoA measurement, ChIP for H3K9ac at promoters, acetate rescue, metabolic flux analysis Cell death & disease Medium 30814486
2019 TIGAR expression is modulated by the transcription factor SP1 (induced by ischemia/reperfusion via ROS and metabolic hormones including adrenaline, hydrocortisone, glucagon); SP1 inhibition or siRNA knockdown blocks ischemia-induced TIGAR upregulation; TIGAR expression is also negatively regulated by insulin via p53 acetylation. MCAO/R mouse model, SP1 inhibitor (mithramycin A), SP1 siRNA, luciferase reporter, chromatin immunoprecipitation, hormone/H2O2 treatment in vivo and in vitro Neurochemistry international Medium 25445985
2011 SP1 transcription factor is indispensable for basal TIGAR promoter activity; a minimal SP1-binding site at -56/-4 bp was identified and SP1 binds the TIGAR promoter in vitro (EMSA) and in vivo (ChIP). 5'-RACE, deletion reporter assays, EMSA, chromatin immunoprecipitation, SP1 knockdown Molecular and cellular biochemistry Medium 21761199
2013 CREB regulates TIGAR expression via a cAMP-response element (CRE) at position -4/+13 of the TIGAR promoter; CREB knockdown reduces promoter activity and TIGAR expression; CREB overexpression or forskolin treatment enhances TIGAR expression. 5'-deletion analysis, site-directed mutagenesis, EMSA, chromatin immunoprecipitation, CREB knockdown/overexpression, luciferase reporter Biochemical and biophysical research communications Medium 24036271
2021 TRIM31 is an E3 ubiquitin ligase for TIGAR; TRIM31 directly interacts with TIGAR and promotes its polyubiquitination and proteasome-dependent degradation; TRIM31 deficiency protects against cerebral ischemia by raising TIGAR levels. Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, TIGAR knockdown rescue, TRIM31 KO in ischemia model Redox biology Medium 34218200
2022 TRIM35 acts as an E3 ubiquitin ligase for TIGAR, interacting with TIGAR and promoting its polyubiquitination and proteasomal degradation; TRIM35 knockdown alleviates renal ischemia-reperfusion injury by elevating TIGAR levels and enhancing mitochondrial fusion. Co-immunoprecipitation, ubiquitination assay, proteasome pathway analysis, TIGAR knockdown rescue, TRIM35 knockdown in renal IRI model International journal of biological macromolecules Medium 35421414
2021 Nuclear TIGAR directly interacts with the antioxidant transcription factor NRF2 and facilitates chromatin recruitment of NRF2, H3K4me3 methylase MLL1, and elongating Pol-II to stimulate expression of NRF2 target genes (including NSD2, NQO1/2, PRDX1, GSTM4), independent of TIGAR's enzymatic activity; nuclear TIGAR also stimulates NSD2 expression leading to elevated global H3K36me2. Co-immunoprecipitation (TIGAR-NRF2), ChIP, enzymatic activity-deficient TIGAR mutant, loss-of-function and gain-of-function experiments, therapeutic resistance assays Acta pharmaceutica Sinica. B Medium 35847493
2024 TIGAR directly binds to TAK1 (TGF-β-activated kinase 1) in macrophages and promotes TRAF6-mediated ubiquitination and auto-phosphorylation of TAK1, enhancing inflammatory NF-κB signaling; residues 152-161 of TIGAR constitute the critical binding motif, and this function is independent of phosphatase activity; interference with TIGAR-TAK1 binding attenuates sepsis in mice. Co-immunoprecipitation (TIGAR-TAK1), ubiquitination assay, domain mapping/mutagenesis (residues 152-161), myeloid-specific Tigar KO in sepsis models (LPS and CLP), pharmacological disruption with 5Z-7-oxozeaenol Nature communications High 38773142
2024 Under prolonged ischemia, mitochondrial TIGAR inhibits succinate dehydrogenase (SDH) activity through post-translational modifications (acetylation and succinylation) of SDH subunit A via direct interaction with SDH A, reducing ROS production and neuronal ferroptosis independently of the PPP-NADPH-GPX4 pathway. TIGAR overexpression/knockdown, mitochondrial fractionation, SDH activity assays, co-immunoprecipitation (TIGAR-SDH A), acetylation/succinylation analysis, enzymatic-activity mutant TIGAR, prolonged OGD model, in vivo stroke model Free radical biology & medicine Medium 38494143
2019 TIGAR inhibits autophagy during ischemia/reperfusion in neurons by activating the mTOR-S6KP70 signaling pathway; TIGAR KO reduces phosphorylated mTOR and S6KP70 levels; autophagy inhibitor 3-MA or NADPH supplementation blocks the exacerbated brain damage seen with TIGAR KO. TIGAR transgenic and knockout mice, MCAO model, primary neurons with OGD/R, western blot for p-mTOR and p-S6KP70, pharmacological rescue with 3-MA and rapamycin Free radical biology & medicine Medium 30978385
2017 TIGAR expression is controlled by the AKT-mTOR-S6K1-eIF4A cap-dependent translation pathway; inhibition of MUC1-C (via GO-203) blocks AKT/mTOR signaling and suppresses eIF4A-mediated TIGAR translation without reducing TIGAR mRNA, leading to decreased GSH and increased ROS. qRT-PCR (TIGAR mRNA unchanged), western blot (TIGAR protein decreased), AKT/mTOR pathway inhibitors, eIF4A inhibition, xenograft model Molecular cancer Medium 28153010
2022 TIGAR induces ferroptosis resistance in colorectal cancer cells via the ROS/AMPK/SCD1 pathway; TIGAR knockdown decreases GSH/GSSG ratio, increases lipid peroxidation/MDA, and TIGAR inhibition represses SCD1 expression in a redox- and AMPK-dependent manner. TIGAR knockdown (siRNA) in CRC cell lines, ferroptosis induction (erastin), lipid peroxidation assays, AMPK inhibitor/activator epistasis, SCD1 expression analysis Free radical biology & medicine Medium 35271998
2015 p53-independent expression of TIGAR occurs in many cancer cell lines and in mouse tissues in vivo; basal TIGAR expression does not depend on p53 or TAp73 in most mouse tissues; stress-induced TIGAR upregulation in mouse intestine after ionizing radiation is also p53- and TAp73-independent. p53 KO mice, TAp73 KO mice, ionizing radiation stress, western blot, tissue analysis Cell death & disease Medium 26247727
2021 TCF19 interacts with p53 and co-regulates TIGAR (and SCO2) transcription; TCF19/p53 form different complexes containing either CBP (for activation) or HDAC1 (for repression) depending on glucose conditions, epigenetically programming TIGAR expression. Co-immunoprecipitation (TCF19-p53), IP/MS, ChIP, TCF19/p53 knockdown, metabolic flux analysis (ECAR/OCR), RNA-seq FASEB journal Medium 34369624
2021 SIRT3 reduces p53 acetylation, leading to decreased TIGAR expression and restored PFKFB3-dependent glycolysis; in high-glucose conditions, loss of SIRT3 increases p53 acetylation and TIGAR expression, impairing glycolysis and promoting ROS/apoptosis in cardiomyocytes. Adenovirus-SIRT3 overexpression, TIGAR siRNA knockdown, p53 acetylation western blot, metabolic assays (glycolysis/ECAR), in vivo db/db diabetic mouse model Journal of the American Heart Association Medium 33586458
2022 Under prolonged ischemia (PPP impaired), TIGAR alleviates oxidative stress through a PPP-independent mechanism by inducing autophagy, which activates Nrf2; Atg7 deletion or Nrf2 silencing abolishes TIGAR neuroprotection in prolonged ischemia; enzymatically inactive mutant TIGAR retains antioxidant effects in this context. Enzymatic mutant TIGAR (no phosphatase activity), G6PD silencing, Atg7 KO mice, Nrf2 knockdown, prolonged OGD model and extended ischemia in vivo Redox biology Medium 35576689
2020 TIGAR supports pancreatic cancer initiation by limiting ROS, while higher ROS in metastasizing PDAC cells drives increased MAPK signaling and a pro-metastatic phenotype; TIGAR expression is higher in premalignant lesions and lower in metastatic tumors; antioxidant treatment reverts the metastatic switch. TIGAR KO in KRAS-driven PDAC mouse model, antioxidant treatment, MAPK pathway analysis, tumor initiation and metastasis assays Cancer cell High 31983610
2019 CRISPR genome-scale loss-of-function screen identifies TIGAR as a modifier of PARP inhibitor sensitivity; TIGAR knockdown enhances olaparib sensitivity via downregulation of BRCA1 and the Fanconi anemia pathway and increases cellular senescence. Genome-scale CRISPR/Cas9 screen, TIGAR knockdown, BRCA1/Fanconi anemia pathway western blot, olaparib sensitivity assay, senescence assay Communications biology Medium 31508509
2020 TIGAR overexpression in ESCC reprograms glucose metabolism from glycolysis toward the glutamine pathway through AMP-activated kinase (AMPK); a catalytically inactive variant of TIGAR does not induce tumor growth in vivo, indicating enzymatic activity is required for metabolic reprogramming and tumor promotion. TIGAR overexpression and KO in ESCC cells and mice, catalytically inactive TIGAR mutant, xenograft and patient-derived xenograft models, metabolic assays (lactate, NADPH, ATP) Theranostics Medium 32206103

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 1626 16839880
2009 Modulation of intracellular ROS levels by TIGAR controls autophagy. The EMBO journal 308 19713938
2006 p53 and metabolism: Inside the TIGAR. Cell 198 16839873
2020 Dynamic ROS Control by TIGAR Regulates the Initiation and Progression of Pancreatic Cancer. Cancer cell 194 31983610
2012 Mitochondrial localization of TIGAR under hypoxia stimulates HK2 and lowers ROS and cell death. Proceedings of the National Academy of Sciences of the United States of America 193 23185017
2013 TIGAR is required for efficient intestinal regeneration and tumorigenesis. Developmental cell 162 23726973
2012 Tp53-induced glycolysis and apoptosis regulator (TIGAR) protects glioma cells from starvation-induced cell death by up-regulating respiration and improving cellular redox homeostasis. The Journal of biological chemistry 137 22887998
2015 MiR-144 inhibits proliferation and induces apoptosis and autophagy in lung cancer cells by targeting TIGAR. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 103 25660220
2014 A TIGAR-regulated metabolic pathway is critical for protection of brain ischemia. The Journal of neuroscience : the official journal of the Society for Neuroscience 95 24872551
2008 Structural and biochemical studies of TIGAR (TP53-induced glycolysis and apoptosis regulator). The Journal of biological chemistry 95 19015259
2022 TIGAR drives colorectal cancer ferroptosis resistance through ROS/AMPK/SCD1 pathway. Free radical biology & medicine 93 35271998
2014 TIGAR, TIGAR, burning bright. Cancer & metabolism 90 24383451
2011 Regulatory role of p53 in cancer metabolism via SCO2 and TIGAR in human breast cancer. Human pathology 90 21820150
2019 TIGAR alleviates ischemia/reperfusion-induced autophagy and ischemic brain injury. Free radical biology & medicine 89 30978385
2015 Opposing effects of TIGAR- and RAC1-derived ROS on Wnt-driven proliferation in the mouse intestine. Genes & development 88 26679840
2019 TIGAR: An Improved Bayesian Tool for Transcriptomic Data Imputation Enhances Gene Mapping of Complex Traits. American journal of human genetics 87 31230719
2011 Inhibition of the MUC1-C oncoprotein induces multiple myeloma cell death by down-regulating TIGAR expression and depleting NADPH. Blood 83 22117045
2014 TIGAR has a dual role in cancer cell survival through regulating apoptosis and autophagy. Cancer research 71 25085248
2016 TP53-inducible Glycolysis and Apoptosis Regulator (TIGAR) Metabolically Reprograms Carcinoma and Stromal Cells in Breast Cancer. The Journal of biological chemistry 67 27803158
2011 TP53 induced glycolysis and apoptosis regulator (TIGAR) knockdown results in radiosensitization of glioma cells. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 65 21864926
2021 Sirtuin 3 Alleviates Diabetic Cardiomyopathy by Regulating TIGAR and Cardiomyocyte Metabolism. Journal of the American Heart Association 63 33586458
2019 TIGAR promotes neural stem cell differentiation through acetyl-CoA-mediated histone acetylation. Cell death & disease 63 30814486
2021 Structure, regulation, and biological functions of TIGAR and its role in diseases. Acta pharmacologica Sinica 61 33510458
2010 p53 and TIGAR regulate cardiac myocyte energy homeostasis under hypoxic stress. American journal of physiology. Heart and circulatory physiology 59 20935145
2015 TIGAR regulates DNA damage and repair through pentosephosphate pathway and Cdk5-ATM pathway. Scientific reports 57 25928429
2017 Targeting MUC1-C inhibits the AKT-S6K1-elF4A pathway regulating TIGAR translation in colorectal cancer. Molecular cancer 55 28153010
2014 Targeting MUC1-C is synergistic with bortezomib in downregulating TIGAR and inducing ROS-mediated myeloma cell death. Blood 55 24632713
2019 Urolithin A gains in antiproliferative capacity by reducing the glycolytic potential via the p53/TIGAR axis in colon cancer cells. Carcinogenesis 52 30418550
2014 TIGAR regulates glycolysis in ischemic kidney proximal tubules. American journal of physiology. Renal physiology 52 25503731
2010 Inhibition of c-Met downregulates TIGAR expression and reduces NADPH production leading to cell death. Oncogene 52 21057531
2012 TIGAR induces p53-mediated cell-cycle arrest by regulation of RB-E2F1 complex. British journal of cancer 49 22782351
2021 The E3 ubiquitin ligase TRIM31 is involved in cerebral ischemic injury by promoting degradation of TIGAR. Redox biology 48 34218200
2019 Potent effects of dioscin against hepatocellular carcinoma through regulating TP53-induced glycolysis and apoptosis regulator (TIGAR)-mediated apoptosis, autophagy, and DNA damage. British journal of pharmacology 48 30710454
2018 TIGAR inhibits ischemia/reperfusion-induced inflammatory response of astrocytes. Neuropharmacology 48 29331305
2017 TIGAR mediates the inhibitory role of hypoxia on ROS production and apoptosis in rat nucleus pulposus cells. Osteoarthritis and cartilage 47 29061494
2016 TIGAR contributes to ischemic tolerance induced by cerebral preconditioning through scavenging of reactive oxygen species and inhibition of apoptosis. Scientific reports 46 27256465
2022 TIGAR alleviates oxidative stress in brain with extended ischemia via a pentose phosphate pathway-independent manner. Redox biology 45 35576689
2019 TP53, TP53 Target Genes (DRAM, TIGAR), and Autophagy. Advances in experimental medicine and biology 45 31776983
2018 Loss of TIGAR Induces Oxidative Stress and Meiotic Defects in Oocytes from Obese Mice. Molecular & cellular proteomics : MCP 45 29776966
2015 Resveratrol inhibits TIGAR to promote ROS induced apoptosis and autophagy. Biochimie 42 26212201
2019 TIGAR Attenuates High Glucose-Induced Neuronal Apoptosis via an Autophagy Pathway. Frontiers in molecular neuroscience 39 31456661
2018 Met is involved in TIGAR-regulated metastasis of non-small-cell lung cancer. Molecular cancer 39 29753331
2018 The diverse role of TIGAR in cellular homeostasis and cancer. Free radical research 39 30284488
2013 Knockdown of TIGAR by RNA interference induces apoptosis and autophagy in HepG2 hepatocellular carcinoma cells. Biochemical and biophysical research communications 39 23817040
2019 Genome-scale CRISPR knockout screen identifies TIGAR as a modifier of PARP inhibitor sensitivity. Communications biology 38 31508509
2014 Identification of TP53-induced glycolysis and apoptosis regulator (TIGAR) as the phosphoglycolate-independent 2,3-bisphosphoglycerate phosphatase. The Biochemical journal 37 24423178
2014 Ischemia/reperfusion-induced upregulation of TIGAR in brain is mediated by SP1 and modulated by ROS and hormones involved in glucose metabolism. Neurochemistry international 37 25445985
2013 ATM-NFκB axis-driven TIGAR regulates sensitivity of glioma cells to radiomimetics in the presence of TNFα. Cell death & disease 37 23640457
2021 NF-κB-Induced Upregulation of miR-146a-5p Promoted Hippocampal Neuronal Oxidative Stress and Pyroptosis via TIGAR in a Model of Alzheimer's Disease. Frontiers in cellular neuroscience 36 33935653
2020 Metabolic remodeling by TIGAR overexpression is a therapeutic target in esophageal squamous-cell carcinoma. Theranostics 36 32206103
2013 Two p53-related metabolic regulators, TIGAR and SCO2, contribute to oroxylin A-mediated glucose metabolism in human hepatoma HepG2 cells. The international journal of biochemistry & cell biology 36 23612020
2017 Downregulation of TIGAR sensitizes the antitumor effect of physapubenolide through increasing intracellular ROS levels to trigger apoptosis and autophagosome formation in human breast carcinoma cells. Biochemical pharmacology 34 28774732
2019 TIGAR regulates mitochondrial functions through SIRT1-PGC1α pathway and translocation of TIGAR into mitochondria in skeletal muscle. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33 30726106
2021 Decitabine Downregulates TIGAR to Induce Apoptosis and Autophagy in Myeloid Leukemia Cells. Oxidative medicine and cellular longevity 32 33532040
2021 TIGAR-V2: Efficient TWAS tool with nonparametric Bayesian eQTL weights of 49 tissue types from GTEx V8. HGG advances 32 35047855
2019 TIGAR impedes compression-induced intervertebral disc degeneration by suppressing nucleus pulposus cell apoptosis and autophagy. Journal of cellular physiology 29 31317559
2015 p53- and p73-independent activation of TIGAR expression in vivo. Cell death & disease 29 26247727
2019 LKB1/p53/TIGAR/autophagy-dependent VEGF expression contributes to PM2.5-induced pulmonary inflammatory responses. Scientific reports 27 31719630
2013 TIGAR: transcript isoform abundance estimation method with gapped alignment of RNA-Seq data by variational Bayesian inference. Bioinformatics (Oxford, England) 27 23821651
2024 TIGAR reduces neuronal ferroptosis by inhibiting succinate dehydrogenase activity in cerebral ischemia. Free radical biology & medicine 26 38494143
2023 Dimethyl fumarate ameliorates parkinsonian pathology by modulating autophagy and apoptosis via Nrf2-TIGAR-LAMP2/Cathepsin D axis. Brain research 26 37315723
2021 TIGAR mitigates atherosclerosis by promoting cholesterol efflux from macrophages. Atherosclerosis 26 33994201
2021 TCF19 and p53 regulate transcription of TIGAR and SCO2 in HCC for mitochondrial energy metabolism and stress adaptation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 26 34369624
2023 TIGAR deficiency induces caspase-1-dependent trophoblasts pyroptosis through NLRP3-ASC inflammasome. Frontiers in immunology 25 37122710
2019 TIGAR Promotes Tumorigenesis and Protects Tumor Cells From Oxidative and Metabolic Stresses in Gastric Cancer. Frontiers in oncology 25 31799200
2018 The ER-alpha mutation Y537S confers Tamoxifen-resistance via enhanced mitochondrial metabolism, glycolysis and Rho-GDI/PTEN signaling: Implicating TIGAR in somatic resistance to endocrine therapy. Aging 24 30573703
2017 TIGAR knockdown radiosensitizes TrxR1-overexpressing glioma in vitro and in vivo via inhibiting Trx1 nuclear transport. Scientific reports 23 28338004
2015 Endogenous level of TIGAR in brain is associated with vulnerability of neurons to ischemic injury. Neuroscience bulletin 23 26219221
2010 An RNA-directed nucleoside anti-metabolite, 1-(3-C-ethynyl-beta-d-ribo-pentofuranosyl)cytosine (ECyd), elicits antitumor effect via TP53-induced Glycolysis and Apoptosis Regulator (TIGAR) downregulation. Biochemical pharmacology 22 20219441
2022 Ginsenoside Rg3 induces apoptosis and inhibits proliferation by down-regulating TIGAR in rats with gastric precancerous lesions. BMC complementary medicine and therapies 21 35840932
2019 TIGAR promotes growth, survival and metastasis through oxidation resistance and AKT activation in glioblastoma. Oncology letters 21 31402948
2016 Distinctive interrelation of p53 with SCO2, COX, and TIGAR in human gastric cancer. Pathology, research and practice 21 27499152
2020 TIGAR reduces smooth muscle cell autophagy to prevent pulmonary hypertension. American journal of physiology. Heart and circulatory physiology 20 32946259
2019 Ablation of cardiac TIGAR preserves myocardial energetics and cardiac function in the pressure overload heart failure model. American journal of physiology. Heart and circulatory physiology 20 30901275
2018 TIGAR knockdown enhanced the anticancer effect of aescin via regulating autophagy and apoptosis in colorectal cancer cells. Acta pharmacologica Sinica 20 29769743
2013 TIGAR is correlated with maximal standardized uptake value on FDG-PET and survival in non-small cell lung cancer. PloS one 20 24363807
2011 SP1 plays a pivotal role for basal activity of TIGAR promoter in liver cancer cell lines. Molecular and cellular biochemistry 20 21761199
2020 TP53-induced glycolysis and apoptosis regulator (TIGAR) ameliorates lysosomal damage in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-mediated mouse model of Parkinson's disease. Toxicology letters 19 33359019
2019 Knockdown of the TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR) Sensitizes Glioma Cells to Hypoxia, Irradiation and Temozolomide. International journal of molecular sciences 19 30823646
2018 The fructose-2,6-bisphosphatase TIGAR suppresses NF-κB signaling by directly inhibiting the linear ubiquitin assembly complex LUBAC. The Journal of biological chemistry 19 29650758
2021 Targeting neuroinflammation to treat cerebral ischemia - The role of TIGAR/NADPH axis. Neurochemistry international 18 34082063
2021 Nuclear TIGAR mediates an epigenetic and metabolic autoregulatory loop via NRF2 in cancer therapeutic resistance. Acta pharmaceutica Sinica. B 18 35847493
2019 Down-regulation of TFAM increases the sensitivity of tumour cells to radiation via p53/TIGAR signalling pathway. Journal of cellular and molecular medicine 18 31062473
2016 Akt mediates TIGAR induction in HeLa cells following PFKFB3 inhibition. FEBS letters 18 27491040
2019 IDH1-R132H mutation radiosensitizes U87MG glioma cells via epigenetic downregulation of TIGAR. Oncology letters 17 31966064
2017 Hypoxia-induced hsa-miR-101 promotes glycolysis by targeting TIGAR mRNA in clear cell renal cell carcinoma. Molecular medicine reports 17 28138701
2008 Identification of TIGAR in the equilibrative nucleoside transporter 2-mediated response to fludarabine in chronic lymphocytic leukemia cells. Haematologica 17 18945750
2024 Disruption of TIGAR-TAK1 alleviates immunopathology in a murine model of sepsis. Nature communications 16 38773142
2022 Cordycepin exhibits anti-fatigue effect via activating TIGAR/SIRT1/PGC-1α signaling pathway. Biochemical and biophysical research communications 16 36399798
2018 The human T-cell leukemia virus type-1 p30II protein activates p53 and induces the TIGAR and suppresses oncogene-induced oxidative stress during viral carcinogenesis. Virology 16 29462755
2020 Dynamic ROS Regulation by TIGAR: Balancing Anti-cancer and Pro-metastasis Effects. Cancer cell 15 32049042
2019 miR-885-5p plays an accomplice role in liver cancer by instigating TIGAR expression via targeting its promoter. Biotechnology and applied biochemistry 14 31119791
2022 The inhibition of TRIM35-mediated TIGAR ubiquitination enhances mitochondrial fusion and alleviates renal ischemia-reperfusion injury. International journal of biological macromolecules 13 35421414
2013 CREB, another culprit for TIGAR promoter activity and expression. Biochemical and biophysical research communications 13 24036271
2022 MiR-652-5p elevated glycolysis level by targeting TIGAR in T-cell acute lymphoblastic leukemia. Cell death & disease 12 35165280
2021 Metformin regulates the Th17/Treg balance by glycolysis with TIGAR in hepatic ischemia-reperfusion injury. Journal of pharmacological sciences 12 33858654
2020 microRNA-144 inhibits cell proliferation and invasion by directly targeting TIGAR in esophageal carcinoma. Oncology letters 12 32256808
2020 TIGAR/AP-1 axis accelerates the division of Lgr5- reserve intestinal stem cells to reestablish intestinal architecture after lethal radiation. Cell death & disease 12 32632140
2023 S1PR2 inhibition mitigates cognitive deficit in diabetic mice by modulating microglial activation via Akt-p53-TIGAR pathway. International immunopharmacology 11 38011768
2022 Gankyrin and TIGAR cooperatively accelerate glucose metabolism toward the PPP and TCA cycle in hepatocellular carcinoma. Cancer science 11 36114745