Sequence of Human Tryptophan 2,3-Dioxygenase (TDO2): Presence of a Glucocorticoid Response-like Element Composed of a GTT Repeat and an Intronic CCCCT Repeat

doi:10.1006/geno.1995.9990

Genomics

Volume 29, Issue 2, September 1995, Pages 390-396

https://doi.org/10.1006/geno.1995.9990 Get rights and content

Abstract

Abnormalities in serotonin levels have been implicated in a wide range of psychiatric disorders. Tryptophan 2,3-dioxygenase is the rate-limiting enzyme in the catabolism of tryptophan, the precursor of serotonin. As such it is a potential major candidate gene in psychiatric genetics. The regulatory, intron, and exon regions of the human TDO2 gene have been sequenced. Twelve exons were identified. The amino acid sequence of the enzyme was 88% homologous to that of the rat. Compared to the rat, the regulatory region of the human TDO2 gene had an insertion of approximately 1064 bp of random DNA beginning at −293 bp and extending to −1357 bp. This displaced the glucocorticoid response element (GRE) occurring at −1174 bp in the rat to −1500 in the human. The proximal GRE at −419 in the rat was missing in the human. However, within the DNA insert there was a GRE-like microsatellite region containing multiple GTT repeats plus additional GT(n) sequences. This could produce several staggered regions of the sequence TGTTGTnnnTGTTGT similar to a GRE consensus sequence of TGTTCAnnnTGTTCT. The intron regions 5′ and 3′ to each exon were sequenced. This allowed each exon to be screened for mutations. This showed a His → Val mutation polymorphism in exon 7. Three introns, 1, 5, and 6, were completely sequenced and examined for polymorphisms. This identified two polymorphisms consisting of G → T and G → A mutations 2 bp apart in intron 6. The 3′ end of intron 5 showed an extensive CCCCT pentanucleotide repeat that was markedly polymorphic. These polymorphisms allow the TDO2 gene to be examined for a possible role in psychiatric disorders.

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The aim of this study was to explore the expression levels and biological significance of TDO2 in colorectal cancer (CRC).
First, we explored the potential oncogenic roles of TDO2 across 33 tumors based on data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Second, we evaluated TDO2 protein expression in 55 CRC tissue samples and 30 cDNA samples by immunohistochemistry and qPCR. Third, we investigated the effect of TDO2 on CRC cells by cell proliferation, wound healing, invasion, and colony formation assays. Finally, we determined the protein that is most closely associated with TDO2 via bioinformatics analysis, enriched the key pathways, and verified them.
The expression level of TDO2 was found to be associated with the tumor clinical stage in CRC. A high expression of TDO2 was associated with a poor outcome in CRC patients. Inhibition of TDO2 expression by RNAi in LoVo and HCT116 cell lines significantly reduced the proliferation, migration, and invasion abilities as well as colony formation abilities of cells. Further, knockdown of TDO2 expression induced inactivation of the TDO2–KYNU–AhR signaling pathway.
The results suggest that TDO2 plays an important role in the progression of CRC. Accordingly, TDO2 is a potential therapeutic target in CRC.
Ozone increases plasma kynurenine-tryptophan ratio and impacts hippocampal serotonin receptor and neurotrophic factor expression: Role of stress hormones
2020, Environmental Research
Air pollution is associated with adverse impacts on the brain, including cognitive decline and increased incidence of dementia, depression and anxiety; however, underlying mechanisms remain unclear. We have shown that both ozone and particulate matter activate the hypothalamic-pituitary-adrenal (HPA) axis, increasing plasma glucocorticoids and altering mRNA profiles in multiple tissues including the brain. HPA axis dysregulation has been associated with central nervous system impacts, including key effects in the hippocampus; accordingly, we hypothesized that pollutant-dependent increases in glucocorticoid levels impact biological pathways relevant to brain health. Fischer-344 rats were treated with metyrapone (0 or 50 mg/kg), a glucocorticoid synthesis inhibitor, and exposed to ozone (0 or 0.8 ppm) for 4 h (n = 5/group) to investigate the role of glucocorticoids in ozone-dependent effects on tryptophan metabolism and expression of serotonin receptors and neurotrophic factors. Ozone increased plasma levels of the tryptophan metabolite kynurenine (~2-fold) and decreased tryptophan levels (~1.2 fold). Hippocampal expression of serotonin receptors exhibited differential regulation following exposure, and expression of key neurotrophic factors (brain-derived neurotrophic factor, vascular endothelial growth factor A, insulin-like growth factor-1, tyrosine kinase receptor B, b-cell lymphoma 2) was decreased. Some, but not all effects were abrogated by metyrapone treatment, suggesting both glucocorticoid-dependent and -independent regulation. Exposure to exogenous corticosterone (10 mg/kg) followed by clean air reproduced the ozone effects that were blocked with metyrapone, confirming the specificity of effects to glucocorticoids. These results indicate that ozone can modify pathways relevant to brain health and establish a role for the HPA axis in mediating these effects.
An integrative analysis of transcriptome-wide association study and mRNA expression profile identified candidate genes for attention-deficit/hyperactivity disorder
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Citation Excerpt :
In addition, a mutation that resulted in increased activity of the TDO2 could resulted in low serotonin levels by increasing degradation of tryptophan (Comings et al., 1995). Single nucleotide polymorphisms in the TDO2 gene may be associated with ADHD (Comings et al., 1995), which was consistent with the results of TWAS. However, further research is still needed to explore the underlying mechanism.
Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, but the genetic mechanism of ADHD remains elusive now.
Tissue specific transcriptome-wide association study (TWAS) of ADHD was performed by FUSION utilizing a genome-wide association study (GWAS) dataset of ADHD (including 20,183 ADHD cases and 35,191 healthy controls) and gene expression reference from brain and blood. Furthermore, the genes identified by TWAS were compared with the differently expressed genes detected by mRNA expression profiles of ADHD rat model and autism spectrum disorders (ASD) patients. Functional enrichment and annotation analysis of the identified genes were performed by DAVID and FUMAGWAS tool.
For brain tissue, TWAS identified 148 genes with P value < 0.05, such as TDO2 (P_TWAS=4.01×10⁻²), CHD1L (P_TWAS=9.64×10⁻³) and KIAA0319L (P_TWAS=4.05×10⁻⁴). Further 11 common genes were examined in the mRNA expression datasets, such as ACSM5 (P_TWAS=3.62×10⁻², P_mRNA=0.005), CCDC24 (P_TWAS=1.49×10⁻², P_mRNA=2.35×10⁻³) and MVP (P_TWAS=5.55×10⁻³, P_mRNA=5.40×10⁻³). Pathway enrichment analysis of the genes identified by TWAS detected 3 pathways for ADHD, including Other glycan degradation (P value=0.021), Viral myocarditis (P value=0.034) and Endocytosis (P value=0.041).
Through integrating GWAS and mRNA expression data, we identified a group of ADHD-associated genes and pathways, providing novel clues for understanding the genetic mechanism of ADHD.
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2019, Cytokine
Citation Excerpt :
There are fewer and sometimes conflicting data about the regulation of TDO2, QPRT, ACMSD by cytokines [50,53,60,80,86]. While it is well known that hormones [87–89] and Trp itself [90] can regulate TDO2 expression, IL-1β has been implicated in its downregulation [52] and TNF in combination with IFNγ in its upregulation [80]. The concentrations of KP-metabolites range from low nanomoles to micromoles [91].
The kynurenine pathway (KP) is the major metabolic route of tryptophan (Trp) metabolism. Indoleamine 2,3-dioxygenase (IDO1), the enzyme responsible for the first and rate-limiting step in the pathway, as well as other enzymes in the pathway, have been shown to be highly regulated by cytokines. Hence, the KP has been implicated in several pathologic conditions, including infectious diseases, psychiatric disorders, malignancies, and autoimmune and chronic inflammatory diseases. Additionally, recent studies have linked the KP with atherosclerosis, suggesting that Trp metabolism could play an essential role in the maintenance of immune homeostasis in the vascular wall. This review summarizes experimental and clinical evidence of the interplay between cytokines and the KP and the potential role of the KP in cardiovascular diseases.
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Corticosteroids (CS) are anti-inflammatory agents that cause extensive pharmacogenomic and proteomic changes in multiple tissues. An understanding of the proteome-wide effects of CS in liver and its relationships to altered hepatic and systemic physiology remains incomplete. Here, we report the application of a functional pharmacoproteomic approach to gain integrated insight into the complex nature of CS responses in liver in vivo. An in-depth functional analysis was performed using rich pharmacodynamic (temporal-based) proteomic data measured over 66 h in rat liver following a single dose of methylprednisolone (MPL). Data mining identified 451 differentially regulated proteins. These proteins were analyzed on the basis of temporal regulation, cellular localization, and literature-mined functional information. Of the 451 proteins, 378 were clustered into six functional groups based on major clinically-relevant effects of CS in liver. MPL-responsive proteins were highly localized in the mitochondria (20%) and cytosol (24%). Interestingly, several proteins were related to hepatic stress and signaling processes, which appear to be involved in secondary signaling cascades and in protecting the liver from CS-induced oxidative damage. Consistent with known adverse metabolic effects of CS, several rate-controlling enzymes involved in amino acid metabolism, gluconeogenesis, and fatty-acid metabolism were altered by MPL. In addition, proteins involved in the metabolism of endogenous compounds, xenobiotics, and therapeutic drugs including cytochrome P450 and Phase-II enzymes were differentially regulated. Proteins related to the inflammatory acute-phase response were up-regulated in response to MPL. Functionally-similar proteins showed large diversity in their temporal profiles, indicating complex mechanisms of regulation by CS.
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Citation Excerpt :
In some cases, antagonists of glucocorticoids, such as RU486 and ketoconazole, have been shown to function as antidepressants [55]. Glucocorticoids also affect the TRP metabolism by increasing the levels of TDO in the liver, and the level of IDO in immune cells [56]. Therefore, alteration of TRP metabolism, neuroendocrine deregulation through the HPA axis, and interference with the IS, appear closely related (Fig. 2) [33].
Toxoplasma gondii is a widespread protozoan parasite infecting approximately one third of the world population. After proliferation of tachyzoites during the acute stage, the parasite forms tissue cysts in various anatomical sites including the Central Nervous tissue, and establishes a chronic infection. Clinical spectrum normally ranges from a completely asymptomatic infection to severe multi-organ involvement. Many studies have suggested T. gondii infection as a risk factor for the development of some neuropsychiatric disorders, particularly schizophrenia. During the last years, a potential link with other neurobiological diseases such as Parkinson disease and Alzheimer disease has also been suggested. This review will focus on neurobiological and epidemiological data relating infection with T. gondii to neuropsychiatric diseases.

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REGULAR ARTICLESequence of Human Tryptophan 2,3-Dioxygenase (TDO2): Presence of a Glucocorticoid Response-like Element Composed of a GTT Repeat and an Intronic CCCCT Repeat

Abstract

REGULAR ARTICLE
Sequence of Human Tryptophan 2,3-Dioxygenase (TDO2): Presence of a Glucocorticoid Response-like Element Composed of a GTT Repeat and an Intronic CCCCT Repeat