View source for TP53-inducible glycolysis and apoptosis regulator

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
The '''TP53-inducible glycolysis and apoptosis regulator''' (TIGAR) also known as '''fructose-2,6-bisphosphatase TIGAR''' is an [[enzyme]] that in humans is encoded by the ''C12orf5'' [[gene]].<ref name="pmid16140933">{{cite journal |vauthors=Jen KY, Cheung VG | title = Identification of novel p53 target genes in ionizing radiation response | journal = Cancer Res | volume = 65 | issue = 17 | pages = 7666–73 |date=Sep 2005 | pmid = 16140933 | doi = 10.1158/0008-5472.CAN-05-1039 | doi-access = free }}</ref><ref name="pmid16839880">{{cite journal |vauthors=Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R, Gottlieb E, Vousden KH | title = TIGAR, a p53-inducible regulator of glycolysis and apoptosis | journal = Cell | volume = 126 | issue = 1 | pages = 107–20 |date=Jul 2006 | pmid = 16839880 | doi = 10.1016/j.cell.2006.05.036 | s2cid = 15006256 | doi-access = free }}</ref><ref name="entrez"/>
TIGAR is a recently discovered enzyme that primarily functions as a regulator of [[glucose]] breakdown in human [[Cell (biology)|cells]]. In addition to its role in controlling glucose degradation, TIGAR activity can allow a cell to carry out [[DNA]] repair, and the degradation of its own [[organelles]]. Finally, TIGAR can protect a cell from death. Since its discovery in 2005 by Kuang-Yu Jen and Vivian G. Cheung, TIGAR has become of particular interest to the scientific community thanks to its active role in many [[cancers]]. Normally, TIGAR manufactured by the body is activated by the [[p53]] tumour suppressor [[protein]] after a cell has experienced a low level of [[DNA damage]] or stress. In some cancers, TIGAR has fallen under the control of other proteins. The hope is that future research into TIGAR will provide insight into new ways to treat cancer.<ref name="Yuang">{{cite journal |vauthors=Jen KY, Cheung VG | title = Identification of novel p53 target genes in ionizing radiation response | journal = Cancer Res. | volume = 65 | issue = 17 | pages = 7666–73 |date=September 2005 | pmid = 16140933 | doi = 10.1158/0008-5472.CAN-05-1039 | doi-access = free }}</ref><ref name="Bensaad">{{cite journal |vauthors=Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R, Gottlieb E, Vousden KH | title = TIGAR, a p53-inducible regulator of glycolysis and apoptosis | journal = Cell | volume = 126 | issue = 1 | pages = 107–20 |date=July 2006 | pmid = 16839880 | doi = 10.1016/j.cell.2006.05.036 | s2cid = 15006256 | doi-access = free }}</ref><ref name="green">{{cite journal |vauthors=Green DR, Chipuk JE | title = p53 and metabolism: Inside the TIGAR | journal = Cell | volume = 126 | issue = 1 | pages = 30–2 |date=July 2006 | pmid = 16839873 | doi = 10.1016/j.cell.2006.06.032 | doi-access = free }}</ref>
This gene is regulated as part of the p53 [[tumor suppressor]] pathway and encodes a protein with sequence similarity to the [[bisphosphate]] domain of the [[glycolytic]] enzyme that degrades fructose-2,6-bisphosphate. The protein functions by blocking glycolysis and directing the pathway into the [[pentose phosphate shunt]]. Expression of this protein also protects cells from DNA damaging [[reactive oxygen species]] and provides some protection from DNA damage-induced [[apoptosis]]. The 12p13.32 region that includes this gene is paralogous to the 11q13.3 region.<ref name="entrez">{{cite web | title = Entrez Gene: C12orf5 chromosome 12 open reading frame 5| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=57103}}</ref>
==Gene==
In humans the TIGAR [[gene]], known as [[C12orf5]], is found on [[chromosome 12]]p13-3, and consists of 6 [[exons]].<ref name="Bensaad" /> The C12orf5 [[mRNA]] is 8237 [[base pairs]] in length.<ref name="NCBI">{{cite web | title =NCBI Summary C12orf5 chromosome 12 open reading frame 5| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=57103}}</ref>
==Discovery==
Jen and Cheung first discovered the c12orf5 gene whilst using computer based searches to find novel p53-regulated genes that were switched on in response to [[ionizing radiation]]. They published their research in Cancer Research in 2005.<ref name="Yuang"/>
Later a study focused wholly on the structure and function of the c12orf5 gene was published in Cell by Karim Bensaad et al., in which c12orf5 was given the name TIGAR in honour of its apparent function.<ref name="Bensaad"/>
==Expression==
TIGAR [[transcription (genetics)|transcription]] is rapidly activated by the p53 [[tumor suppressor gene|tumour suppressor]] protein in response to low levels of cellular stress, such as that caused by exposure to low doses of [[UV]].<ref name="Madan">{{cite journal |vauthors=Madan E, Gogna R, Kuppusamy P, Bhatt M, Pati U, Mahdi AA | title = TIGAR induces p53-mediated cell-cycle arrest by regulation of RB-E2F1 complex | journal = Br. J. Cancer | volume = 107 | issue = 3 | pages = 516–26 |date=July 2012 | pmid = 22782351 | doi = 10.1038/bjc.2012.260 | pmc=3405207}}</ref> However, under high levels of cellular stress TIGAR expression decreases.<ref name="Madan"/> P53, a [[transcription factor]], can bind two sites within the human TIGAR gene to activate expression.<ref name="Bensaad"/><ref name="Gogna"/> One site is found within the first [[intron]], and binds p53 with high affinity.<ref name="Bensaad"/><ref name="Gogna"/> The second is found just prior to the first exon, binds p53 with low affinity,<ref name="Bensaad"/><ref name="Gogna"/> and is conserved between mice and humans.<ref name="Bensaad"/>
TIGAR expression can be regulated by other non-p53 mechanisms in [[cell culture|tumour cell lines]].<ref name="Bensaad"/>
==Structure==
[[File:Human TIGAR.png|300px|thumb | alt=A cartoon of the tertiary structure of TIGAR | A cartoon of the tertiary structure of TIGAR.]]
TIGAR is approximately 30kDa <ref name="Bensaad"/> and has a [[tertiary structure]] that is similar to the [[HAMP domain|histidine phosphatase]] fold.<ref name="Li">{{cite journal |vauthors=Li H, Jogl G | title = Structural and biochemical studies of TIGAR (TP53-induced glycolysis and apoptosis regulator) | journal = J. Biol. Chem. | volume = 284 | issue = 3 | pages = 1748–54 |date=January 2009 | pmid = 19015259 | pmc = 2615519 | doi = 10.1074/jbc.M807821200 | doi-access = free }}</ref> The core of TIGAR is made up of an α-β-α sandwich, which consists of a six-stranded [[β sheet]] surrounded by 4 [[α helices]].<ref name="Li"/> Additional α helices and a long loop are built around the core to give the full enzyme.<ref name="Li"/> TIGAR has an [[active site]] that is structurally similar to that of PhoE (a bacterial phosphatase enzyme) and functionally similar to that of [[fructose-2,6-bisphosphatase]].
The bis-phosphatase-like active site of TIGAR is positively charged, and [[catalyse]]s the removal of [[phosphate]] groups from other molecules.<ref name="Bensaad"/><ref name="Li"/> In contrast to Fructose-2,6-Bisphosphatase, TIGAR's active site is open and accessible like that of PhoE.<ref name="Li"/> The site contains 3 crucial [[amino acids]] (2 histidines and 1 [[glutamic acid]]<ref name="Bensaad"/>) that are involved in the [[phosphatase]] reaction. These 3 residues are known collectively as a [[catalytic triad]],<ref name="Bensaad"/> and are found in all enzymes belonging to the [[phosphoglyceromutase]] branch of the histidine phosphatase superfamily.<ref name="Bensaad"/><ref name="Li"/> One of the histidine residues is [[electrostatics|electrostatically]] bound to a negatively charged phosphate. A second phosphate is bound elsewhere in the active site.<ref name="Li"/>
== Function ==
TIGAR activity can have multiple cellular effects. TIGAR acts as a direct regulator of [[fructose-2,6-bisphosphate]] levels and [[HK2|hexokinase 2]] activity, and this can lead indirectly to many changes within the cell in a chain of biochemical events. TIGAR is a fructose bisphosphatase which activates p53, in results of inhibiting the expression of glucose transporter and also regulating the expression of hexokinase and phosphoglycerate mutase. TIGAR also inhibit the Phosphofructokinase (PFK) by lowering the level of fructose-2,6,bisphosphate, therefore, glycolysis is inhibited and pentose phosphate pathway is promoted.<ref name=":0" />
=== Fructose-2,6-bisphosphate regulation ===
TIGAR decreases cellular fructose-2,6-bisphosphate levels.<ref name="Bensaad"/><ref name="Gogna">{{cite journal |vauthors=Madan E, Gogna R, Bhatt M, Pati U, Kuppusamy P, Mahdi AA | title = Regulation of glucose metabolism by p53: emerging new roles for the tumor suppressor | journal = Oncotarget | volume = 2 | issue = 12 | pages = 948–57 |date=December 2011 | pmid = 22248668 | pmc = 3282098 | doi = 10.18632/oncotarget.389}}</ref> It catalyses the removal of a phosphate group from fructose-2,6-bisphosphate (F-2,6-BP):<ref name="Bensaad"/><ref name="Gogna"/>
Fructose-2,6-Bisphosphate->Fructose-6-phosphate (F-6-P) + phosphate
F-2,6-BP is an [[allosteric]] regulator of cellular [[glucose metabolism]] pathways. Ordinarily F-2,6-BP binds to and increases the activity of [[phosphofructokinase 1]]. Phosphofructokinase-1 catalyses the addition of a phosphate to F-6-P to form Fructose-1,6-bisphosphate (F-1,6-BP). This is an essential step in the [[glycolysis]] pathway, which forms the first part of [[aerobic respiration]] in [[mammals]]. F-2,6-BP also binds to and decreases the activity of fructose-1,6-bisphosphatase.<ref name="Bensaad"/> Fructose-1,6-bisphosphatase catalyses the removal of phosphate from F-1,6-BP to form F-6-P. This reaction is part of the [[gluconeogenesis]] pathway, which synthesizes [[glucose]], and is the reverse of glycolysis.<ref name="isbn0-471-19350-X">{{cite book |vauthors=Voet JG, Voet D | title = Biochemistry |url=https://archive.org/details/biochemistry00voet_1 |url-access=registration | publisher = J. Wiley & Sons | location = New York | year = 2004 | isbn = 0-471-19350-X | edition = 3  }}</ref> When TIGAR decreases F-2,6-BP levels, phosphofructokinase becomes less active whilst fructose-1,6-bisphosphatase activity increases.<ref name="Bensaad"/><ref name="Gogna"/> Fructose-6-phosphate levels build up,<ref name="Bensaad"/><ref name="Gogna"/> which has multiple effects inside the cell:
*The rate of glycolysis decreases<ref name="Bensaad"/><ref name="Gogna"/>
*The rate of gluconeogenesis increases<ref name="Bensaad"/>
*Excess fructose-6-phosphate is converted to glucose-6-phosphate in an [[isomerization]] reaction <ref name="Bensaad"/>
*Excess glucose-6-phosphate enters the [[pentose phosphate pathway]]. This ultimately leads to the removal of [[reactive oxygen species]] (ROS) in the cell<ref name="Bensaad"/><ref name="Gogna"/>
* The removal of ROS helps to prevent [[apoptosis]] (cell suicide), and may also reduce build-up of [[DNA damage]] over time.<ref name="Bensaad"/><ref name="Gogna"/>
=== DNA damage response and cell cycle arrest ===
TIGAR can act to prevent a cell progressing through the stages of its growth and division cycle by decreasing cellular [[Adenosine triphosphate|ATP]] levels.<ref name="Madan"/> This is known as [[cell cycle]] arrest.<ref name="Madan"/> This function of TIGAR forms part of the p53 mediated [[DNA damage]] response where, under low levels of cellular stress, p53 initiates [[cell cycle checkpoint|cell cycle arrest]] to allow the cell time for repair.<ref name="Gogna"/><ref name="Vousden">{{cite journal |vauthors=Vousden KH, Lu X | title = Live or let die: the cell's response to p53 | journal = Nat. Rev. Cancer | volume = 2 | issue = 8 | pages = 594–604 |date=August 2002 | pmid = 12154352 | doi = 10.1038/nrc864| s2cid = 6412605 | url = https://zenodo.org/record/1233502 }}</ref><ref name="Jackson">{{cite journal |vauthors=Jackson SP, Bartek J | title = The DNA-damage response in human biology and disease | journal = Nature | volume = 461 | issue = 7267 | pages = 1071–8 |date=October 2009 | pmid = 19847258 | pmc = 2906700 | doi = 10.1038/nature08467 | bibcode = 2009Natur.461.1071J }}</ref> Under high levels of cellular stress, p53 initiates apoptosis instead.<ref name="Gogna"/><ref name="Vousden"/><ref name="Jackson"/>
In non-resting cells, the cell cycle consists of G0 -> G1 -> S -> G2 -> M phases, and is tightly regulated at checkpoints between the phases.<ref name="Elledge">{{cite journal | author = Elledge SJ | title = Cell cycle checkpoints: preventing an identity crisis | journal = Science | volume = 274 | issue = 5293 | pages = 1664–72 |date=December 1996 | pmid = 8939848 | doi = 10.1126/science.274.5293.1664 | bibcode = 1996Sci...274.1664E | s2cid = 39235426 }}</ref> If the cell has undergone stress, certain proteins are expressed that will prevent the specific sequence of [[macromolecular]] interactions at the checkpoint required for progression to the next phase.<ref name="Vousden"/><ref name="Jackson"/><ref name="Elledge"/>
TIGAR activity can prevent cells progressing into S phase through a checkpoint known in humans as the [[restriction point]]. At the very start of [[G1 phase]], a protein called [[retinoblastoma]] (Rb) exists in an un-phosphorylated state. In this state, Rb binds to a protein transcription factor [[E2F]] and prevents E2F from activating transcription of proteins essential for [[S-phase]]. During a normal cell cycle, as G1 progresses, Rb will become phosphorylated in a specific set of sequential steps by proteins called [[cyclin dependent kinases]] (cdks) bound to [[cyclin]] proteins. The specific complexes that phosphorylate Rb are [[cyclin D]]-[[cdk4]] and [[cyclin E]]-[[cdk2]].<ref name="Henley">{{cite journal |vauthors=Henley SA, Dick FA | title = The retinoblastoma family of proteins and their regulatory functions in the mammalian cell division cycle | journal = Cell Div | volume = 7 | issue = 1 | pages = 10 | year = 2012 | pmid = 22417103 | pmc = 3325851 | doi = 10.1186/1747-1028-7-10 | doi-access = free }}</ref>
When Rb has been phosphorylated many times, it dissociates from E2F. E2F is free to activate expression of S-phase genes.<ref name="Henley"/> TIGAR can indirectly prevent a cell passing through the Restriction Point by keeping Rb unphosphorylated.<ref name="Madan"/>
When expressed, TIGAR decreases cellular ATP levels through its phosphatase activity.<ref name="Madan"/> Less ATP is available for Rb phosphorylation, so Rb remains un-phosphorylated and bound to E2F, which cannot activate S phase genes.<ref name="Madan"/> Expression of cyclin D, ckd4, cyclin E and cdk2 decreases when TIGAR is active, due to a lack of ATP essential for their transcription and [[Translation (biology)|translation]].<ref name="Madan"/> This TIGAR activity serves to arrest cells in G1.<ref name="Madan"/>
=== Activity of hexokinase 2 ===
Under low oxygen conditions known as [[hypoxia (medical)|hypoxia]], a small amount of TIGAR travels to the [[mitochondria]] and increases the activity of Hexokinase 2 (HK2) by binding to it<ref name="Cheung">{{cite journal |vauthors=Cheung EC, Ludwig RL, Vousden KH | title = Mitochondrial localization of TIGAR under hypoxia stimulates HK2 and lowers ROS and cell death | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 109 | issue = 50 | pages = 20491–6 |date=December 2012 | pmid = 23185017 | pmc = 3528527 | doi = 10.1073/pnas.1206530109 | bibcode = 2012PNAS..10920491C | doi-access = free }}</ref>
During hypoxia, a protein called [[HIF1A|Hif1α]] is activated and causes TIGAR to re-localise from the [[cytoplasm]] to the outer mitochondrial [[membrane]].<ref name="Cheung"/> Here, HK2 is bound to an [[anion]] channel in the outer mitochondrial membrane called VDAC.<ref name="Pastorino">{{cite journal |vauthors=Pastorino JG, Shulga N, Hoek JB | title = Mitochondrial binding of hexokinase II inhibits Bax-induced cytochrome c release and apoptosis | journal = J. Biol. Chem. | volume = 277 | issue = 9 | pages = 7610–8 |date=March 2002 | pmid = 11751859 | doi = 10.1074/jbc.M109950200  | doi-access = free }}</ref> TIGAR binds hexokinase 2 and increases its activity by an as yet unknown mechanism.<ref name="Cheung"/>
Hexokinase 2 (HK2) carries out the following reaction:
Glucose + ATP -> Glucose-6-phosphate + ADP <ref name="Cheung"/><ref name="Pastorino"/><ref name="dasilva">{{cite journal |vauthors=da-Silva WS, Gómez-Puyou A, de Gómez-Puyou MT, Moreno-Sanchez R, De Felice FG, de Meis L, Oliveira MF, Galina A | title = Mitochondrial bound hexokinase activity as a preventive antioxidant defense: steady-state ADP formation as a regulatory mechanism of membrane potential and reactive oxygen species generation in mitochondria | journal = J. Biol. Chem. | volume = 279 | issue = 38 | pages = 39846–55 |date=September 2004 | pmid = 15247300 | doi = 10.1074/jbc.M403835200 | doi-access =  free}}</ref>
HK2 is believed to maintain the mitochondrial [[membrane potential]] by keeping ADP levels high.<ref name="dasilva"/> It also prevents apoptosis in several ways: it reduces mitochondrial ROS levels,<ref name="Cheung"/><ref name="dasilva"/> and it prevents apoptosis-causing protein [[Bcl-2-associated X protein|Bax]] from creating a channel with VDAC.<ref name="Pastorino"/> This stops [[cytochrome C]] protein passing out through VDAC into the cytoplasm where it triggers apoptosis via a [[caspase]] protein cascade.<ref name="Pastorino"/>
TIGAR does not re-localise to the mitochondria and bind HK2 under normal cellular conditions,<ref name="Cheung"/> or if the cell is starved of glucose.<ref name="Cheung"/> Re-localisation to the mitochondria does not require TIGAR's phosphatase domain.<ref name="Cheung"/> Instead 4 amino acids at the [[C-terminal]] end of TIGAR are essential.<ref name="Cheung"/>
=== Protection from apoptosis ===
Increased expression of TIGAR protects cells from oxidative-stress induced apoptosis <ref name="Valko">{{cite journal |vauthors=Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J | title = Free radicals and antioxidants in normal physiological functions and human disease | journal = Int. J. Biochem. Cell Biol. | volume = 39 | issue = 1 | pages = 44–84 | year = 2007 | pmid = 16978905 | doi = 10.1016/j.biocel.2006.07.001 }}</ref> by decreasing the levels of ROS.<ref name="Bensaad"/> TIGAR can indirectly reduce ROS in two distinctive ways. The [[intracellular]] environment of the cell will determine which of these two modes of TIGAR action is more prevalent in the cell at any one time.<ref name="Bensaad"/><ref name="Cheung"/>
The fructose-2,6-bisphosphatase activity of TIGAR reduces ROS by increasing the activity of the Pentose Phosphate Pathway (PPP).<ref name="Bensaad"/> Glucose-6-phosphate builds up due to de-phosphorylation of F-2,6-BP by TIGAR and enters the PPP.<ref name="Bensaad"/>
This causes the PPP to generate more [[nicotinamide adenine dinucleotide]] ([[NADPH]]).<ref name="Bensaad"/><ref name="Fico">{{cite journal |vauthors=Fico A, Paglialunga F, Cigliano L, Abrescia P, Verde P, Martini G, Iaccarino I, Filosa S | title = Glucose-6-phosphate dehydrogenase plays a crucial role in protection from redox-stress-induced apoptosis | journal = Cell Death Differ. | volume = 11 | issue = 8 | pages = 823–31 |date=August 2004 | pmid = 15044966 | doi = 10.1038/sj.cdd.4401420 | doi-access = free }}{{Retracted|doi=10.1038/s41418-022-01111-y|pmid=36635348}}</ref> NADPH is a carrier of [[electrons]] that is used by the cell as a [[reducing agent]] in many [[anabolism|anabolic reactions]]. NADPH produced by the PPP passes electrons to an [[oxidized]] [[glutathione]] molecule (GSSG) to form reduced glutathione (GSH).<ref name="Bensaad"/><ref name="Fico"/>
GSH becomes the [[reducing agent]], and passes electrons on to the ROS [[hydrogen peroxide]] to form harmless water in the reaction:
GSH + H<sub>2</sub>O<sub>2</sub> -> H<sub>2</sub>O + GSSG <ref name="Bensaad"/><ref name="Fico"/>
The decrease in H<sub>2</sub>O<sub>2</sub> as a result of TIGAR activity protects against apoptosis.<ref name="Bensaad"/><ref name="Fico"/>
TIGAR also reduces ROS by increasing the activity of HK2. HK2 reduces ROS levels indirectly by keeping [[Adenosine diphosphate|ADP]] levels at the outer mitochondrial membrane high. If ADP levels fall, the rate of respiration decreases and causes the [[electron transport chain]] to become over-reduced with excess electrons. These excess electrons pass to oxygen and form ROS.<ref name="Cheung"/>
The action of the TIGAR/HK2 complex only protects cells from apoptosis under low oxygen conditions. Under normal or glucose starved conditions, TIGAR mediated protection from apoptosis comes from its bis-phosphatase activity alone.<ref name="Cheung"/>
TIGAR cannot prevent apoptosis via death pathways that are independent from ROS and p53.<ref name="Bensaad"/> In some cells, TIGAR expression can push cells further towards apoptosis.<ref name="Bensaad"/>
[[Interleukin]] 3 (IL-3) is a [[growth factor]] that can bind to [[receptor (biochemistry)|receptor]]s on a cell's surface and tells the cell to survive and grow.<ref name="Heiden">{{cite journal |author3-link=Jeffrey Rathmell|vauthors=Vander Heiden MG, Plas DR, Rathmell JC, Fox CJ, Harris MH, Thompson CB | title = Growth factors can influence cell growth and survival through effects on glucose metabolism | journal = Mol. Cell. Biol. | volume = 21 | issue = 17 | pages = 5899–912 |date=September 2001 | pmid = 11486029 | pmc = 87309 | doi = 10.1128/MCB.21.17.5899-5912.2001 }}</ref> When IL-3 dependent cell lines are deprived of IL-3 they die<ref name="Heiden"/> due to decreased uptake and metabolism of glucose.<ref name="Heiden"/> When TIGAR is overexpressed in IL-3 deprived cells the rate of glycolysis decreases further which enhances the apoptosis rate.<ref name="Bensaad"/>
=== Autophagy ===
Autophagy is when a cell digests some of its own organelles by lysosomal degradation. Autophagy is employed to remove damaged organelles, or under starvation conditions to provide additional nutrients. Normally, autophagy occurs by the TSC-Mtor pathway, but can be induced by ROS. TIGAR, even at very low levels, inhibits autophagy by decreasing ROS levels. The mechanism by which TIGAR does this is independent from the Mtor pathway, but the exact details are unknown.<ref name="autophagy">{{cite journal |vauthors=Bensaad K, Cheung EC, Vousden KH | title = Modulation of intracellular ROS levels by TIGAR controls autophagy | journal = EMBO J. | volume = 28 | issue = 19 | pages = 3015–26 |date=October 2009 | pmid = 19713938 | pmc = 2736014 | doi = 10.1038/emboj.2009.242 }}</ref>
==Possible roles in cancer==
TIGAR can promote development or inhibition of several [[cancers]] depending on the cellular context.<ref name="Gogna"/><ref name="Wanka">{{cite journal |vauthors=Wanka C, Steinbach JP, Rieger J | title = Tp53-induced glycolysis and apoptosis regulator (TIGAR) protects glioma cells from starvation-induced cell death by up-regulating respiration and improving cellular redox homeostasis | journal = J. Biol. Chem. | volume = 287 | issue = 40 | pages = 33436–46 |date=September 2012 | pmid = 22887998 | doi = 10.1074/jbc.M112.384578 | pmc=3460445| doi-access = free }}</ref><ref name="yin">{{cite journal |vauthors=Yin L, Kosugi M, Kufe D | title = Inhibition of the MUC1-C oncoprotein induces multiple myeloma cell death by down-regulating TIGAR expression and depleting NADPH | journal = Blood | volume = 119 | issue = 3 | pages = 810–6 |date=January 2012 | pmid = 22117045 | pmc = 3265204 | doi = 10.1182/blood-2011-07-369686  }}</ref><ref name="Won">{{cite journal |vauthors=Won KY, Lim SJ, Kim GY, Kim YW, Han SA, Song JY, Lee DK | title = Regulatory role of p53 in cancer metabolism via SCO2 and TIGAR in human breast cancer | journal = Hum. Pathol. | volume = 43 | issue = 2 | pages = 221–8 |date=February 2012 | pmid = 21820150 | doi = 10.1016/j.humpath.2011.04.021 }}</ref> TIGAR can have some effect on three characteristics of cancer; the ability to evade apoptosis, uncontrolled [[cell division]], and altered metabolism.<ref name="Gogna"/><ref name="Wanka"/><ref name="yin"/><ref name="Won"/><ref name="Hanahan">{{cite journal |vauthors=Hanahan D, Weinberg RA | title = Hallmarks of cancer: the next generation | journal = Cell | volume = 144 | issue = 5 | pages = 646–74 |date=March 2011 | pmid = 21376230 | doi = 10.1016/j.cell.2011.02.013 | doi-access = free }}</ref> Many cancer cells have altered metabolism where the rate of glycolysis and [[anaerobic respiration]] are very high whilst [[cellular respiration|oxidative respiration]] is low, which is called the [[Warburg Effect (oncology)|Warburg Effect]] (or [[aerobic glycolysis]]).<ref name="Hanahan"/> This allows cancer cells to survive under low oxygen conditions, and use molecules from respiratory pathways to synthesise amino acids and [[nucleic acids]] to maintain rapid growth.<ref name="Hanahan"/>
In [[Glioma]], a type of brain cancer, TIGAR can be over-expressed where it has [[oncogenic]]-like effects.<ref name="Wanka"/> In this case, TIGAR acts to maintain energy levels for increased growth by increasing respiration (conferring altered metabolism), and also protects glioma cells against hypoxia-induced apoptosis by decreasing ROS (conferring evasion of apoptosis).<ref name="Wanka"/> TIGAR is also overexpressed in some breast cancers.<ref name="Won"/>
In [[multiple myeloma]], TIGAR expression is linked to the activity of MUC-1. MUC-1 is an [[oncoprotein]] that is overexpressed in multiple myeloma and protects these cells from ROS-induced apoptosis by maintaining TIGAR activity. When MUC-1 activity is removed, levels of TIGAR decline and cells undergo ROS-induced apoptosis.<ref name="yin"/>
In a type of head and neck cancer known as [[nasopharyngeal]] cancer, the onco-protein kinase [[c-Met]] maintains TIGAR expression. TIGAR increases glycolytic rate and NADPH levels which allows the cancer cells to maintain fast growth rates.<ref name="Lui">{{cite journal |vauthors=Lui VW, Wong EY, Ho K, Ng PK, Lau CP, Tsui SK, Tsang CM, Tsao SW, Cheng SH, Ng MH, Ng YK, Lam EK, Hong B, Lo KW, Mok TS, Chan AT, Mills GB | title = Inhibition of c-Met downregulates TIGAR expression and reduces NADPH production leading to cell death | journal = Oncogene | volume = 30 | issue = 9 | pages = 1127–34 |date=March 2011 | pmid = 21057531 | pmc = 3428712 | doi = 10.1038/onc.2010.490 }}</ref>
However, TIGAR may also have an inhibitory effect on cancer development by preventing cellular proliferation through its role in p53 -mediated cell cycle arrest.<ref name="Gogna"/>
== References ==
{{Reflist|35em|refs=
<ref name=":0">{{Cite book|title=Biochemistry|last=Garrett|first=Reginald|publisher=Cengage Learning|year=2016|isbn=978-1305577206|location=Stamford, CT|pages=631}}</ref>
}}
== Further reading ==
{{refbegin|35em}}
* {{cite journal |vauthors=Green DR, Chipuk JE | title = p53 and metabolism: Inside the TIGAR | journal = Cell | volume = 126 | issue = 1 | pages = 30–2 |date=July 2006 | pmid = 16839873 | doi = 10.1016/j.cell.2006.06.032 | doi-access = free }}
* {{cite journal | title = Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23 | journal = Nat. Genet. | volume = 26 | issue = 3 | pages = 345–8 |date=November 2000 | pmid = 11062477 | doi = 10.1038/81664 | last1 = White | first1 = Kenneth E. | last2 = Evans | first2 = Wayne E. | last3 = O'Riordan | first3 = Jeffery L.H. | last4 = Speer | first4 = Marcy C. | last5 = Econs | first5 = Michael J. | last6 = Lorenz-Depiereux | first6 = Bettina | last7 = Grabowski | first7 = Monika | last8 = Meitinger | first8 = Thomas | last9 = Strom | first9 = Tim M. | s2cid = 38870810 }}
* {{cite journal |vauthors=Hartley JL, Temple GF, Brasch MA | title = DNA cloning using in vitro site-specific recombination | journal = Genome Res. | volume = 10 | issue = 11 | pages = 1788–95 |date=November 2000 | pmid = 11076863 | pmc = 310948 | doi = 10.1101/gr.143000 }}
* {{cite journal |vauthors=Katoh Y, Katoh M | title = Comparative genomics on mammalian Fgf6-Fgf23 locus | journal = Int. J. Mol. Med. | volume = 16 | issue = 2 | pages = 355–8 |date=August 2005 | pmid = 16012775 | doi = 10.3892/ijmm.16.2.355}}
{{refend}}
[[Category:Apoptosis]]
[[Category:Glycolysis]]
[[Category:Human proteins]]