Departament de Ciencies Fisiologiques II, Campus de Bellvitge, Universitat de Barcelona, Feixa Llarga s\\\/n, 08907, LHospitalet de Llobregat, Barcelona, Spain
Activation and regulation
TIGAR belongs to that group of TP53 target genes that become rapidly activated by low levels of stress. There are two possible TP53 binding sites in TIGAR gene: one upstream of the first exon (BS1) and one within the 1st intron (BS2), which is the most efficient one and has been validated by chromatin immunoprecipitation (ChIP) analysis (Bensaad et al., 2006).
In an experimental approach, TIGAR was induced by Actinomycin D and Adriamycin (Bensaad et al., 2006), two well-known activators of TP53, and also by Nutlin-3a, an antagonist of Mdm2 (Hasegawa et al., 2009). Other stimuli that have been described to trigger TIGAR expression are radiotherapy (Peña-Rico et al., 2011), glutamine (Ko et al., 2011), chemotherapy (Madan et al., 2012), UV light (Madan et al., 2012), TNFα and radiotherapy mimetics (Sinha et al., 2013).
When DNA damage occurs, TP53 is expressed either to repair DNA or lead the cell towards apoptosis. High ROS levels can compromise DNA stability which, in turn, could help cells to accumulate mutations and become tumorigenic. As TIGAR reduces ROS levels, it has been proposed as a tumor suppressor gene, although it should be taken into account that, as TIGAR can help tumor cells survival, it could act as an oncogene in some situations. TP53 is able to suppress tumor development when mechanisms of apoptosis, senescence and cell-cycle arrest are impeded. This supports the idea that metabolism, and thereby TIGAR, has a key role in cancer development (Li et al., 2012; Valente et al., 2013).
TIGAR expression can also be modulated in a TP53 independent manner, as results from studies with the TP53 null T98G and H1299 cell lines suggest (Bensaad et al., 2006; Peña-Rico et al., 2011). The mechanisms implicated in the regulation of TIGAR expression in the absence of TP53 are unclear. The CRE-binding protein (CREB) has been described to regulate TIGAR expression through a CRE-binding site at the TIGAR promoter, which was first annotated by bioinformatic analysis and then confirmed by electrophoretic mobility shift assay (EMSA) and ChIP. CREB knockdown reduced enhanced promoter activity and TIGAR expression; whereas CREB overexpression resulted in enhanced promoter activity and TIGAR expression levels (Zou et al., 2013). Another transcription factor, SP1, was found to bind to TIGAR promoter in a SP1-binding site located in a very short region (-56/-4) both in vitro and in vivo, and was considered a key factor for proper basal activity of TIGAR promoter (Zou et al., 2012). Recently, some authors have identified HIF-1α as a potential regulator of SCO2 and TIGAR gene expression suggesting the involvement of P300/CBP-associated factor (PCAF) in differential recruitment of HIF-1α and p53 to the promoter of TIGAR and/or SCO2 genes in response of hypoxia in tumoral cells (Rajendran et al., 2013).
Chromosomal rearrangements: copy number variants
Some alterations affecting TIGAR genome region have been described in patients, some of them showed phenotypic effects. Gain of 12:189578-34178209 resulted in hydronephrosis, micrognathia, edema, depressed nasal bridge, tricuspid regurgitation and diaphragmatic eventration. Patients with gain of 12:189561-41878937 suffered global developmental delay. The ones with gain of 12:230361-20643702 showed intellectual disability and electroencephalogram with localized low amplitude activity, whereas gain of 12:191619-8327369 resulted in macroencephaly, visual impairment, intellectual disability, muscular hipotonia, and seizures.
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There are 878 SNP variants described but none of them have clinical significance described (GeneCards).
Helga Simon ; Ana Rodríguez-García ; Àurea Navarro-Sabaté ; Pere Fontova ; Ramon Bartrons ; Anna Manzano
TIGAR (chromosome 12 open reading frame 5)
Atlas Genet Cytogenet Oncol Haematol. 2013-12-01
Online version: http://atlasgeneticsoncology.org/gene/50684/tigar-(chromosome-12-open-reading-frame-5)