Gene Summary

Gene:TCEA1; transcription elongation factor A1
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:transcription elongation factor A protein 1
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (19)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Intracellular Signaling Peptides and Proteins
  • Oncogene Fusion Proteins
  • IFIT1 protein, human
  • DNA Helicases
  • MCM2 protein, human
  • Gene Ontology
  • Meningioma
  • Adenoma
  • Ubiquitin-Conjugating Enzymes
  • Salivary Glands
  • Biomarkers, Tumor
  • XRCC5 protein, human
  • Cultured Cells
  • Salivary Gland Cancer
  • Neuroblastoma
  • Retinoblastoma
  • Disease Progression
  • Chromosome 12
  • Carcinogenesis
  • Proteins
  • Promoter Regions
  • Neoplasm Proteins
  • MCM7 protein, human
  • SEC31A protein, human
  • Cell Line
  • Down-Regulation
  • polypeptide N-acetylgalactosaminyltransferase
  • Gene Expression
  • Translocation
  • Mice, Inbred BALB C
  • Chromatin
  • transcription factor S-II
  • Ku Autoantigen
  • DNA-Binding Proteins
  • Long Noncoding RNA
  • Chromosome 8
  • cdc25 Phosphatases
  • Transcriptional Elongation Factors
  • Cancer Gene Expression Regulation
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TCEA1 (cancer-related)

Chovanec M, Cierna Z, Miskovska V, et al.
βcatenin is a marker of poor clinical characteristics and suppressed immune infiltration in testicular germ cell tumors.
BMC Cancer. 2018; 18(1):1062 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: WNT/βcatenin (WNTβ) pathway is activated in early stages of embryonic development. We aimed to evaluate the significance of βcatenin in germ cell tumors (GCTs) and explore associations with the inflamed environment.
METHODS: Surgical specimens from 247 patients were analyzed. Βcatenin expression was detected in the tumor tissue by immunohistochemistry and correlated with clinical characteristics, outcome, PD-L1 expression and systemic immune-inflammation index (SII). The Ingenuity Pathway Analysis (IPA) was used to investigate the immune-cell related effects of βcatenin and PD-L1 encoding genes.
RESULTS: βcatenin was expressed in 86.2% of GCTs. The expression in seminomas was significantly lower compared to all subtypes of non-seminoma (all P <  0.0001). A high expression (weighted histoscore > 150) was associated with primary mediastinal non-seminoma (P = 0.035), intermediate/poor risk disease (P = 0.033) and high tumor markers (P = 0.035). We observed a positive correlation with the PD-L1 in tumor and an inverse correlation with the SII. IPA uncovered relationships of CTNNB (βcatenin) and CD274 (PD-L1) genes and their effects on differentiation, proliferation and activation of lymphocyte subtypes.
CONCLUSION: Herein, we showed that βcatenin is associated with male adult GCT characteristics as well as supressed immune environment.

Chai P, Jia R, Jia R, et al.
Dynamic chromosomal tuning of a novel GAU1 lncing driver at chr12p13.32 accelerates tumorigenesis.
Nucleic Acids Res. 2018; 46(12):6041-6056 [PubMed] Free Access to Full Article Related Publications
Aberrant chromatin transformation dysregulates gene expression and may be an important driver of tumorigenesis. However, the functional role of chromosomal dynamics in tumorigenesis remains to be elucidated. Here, using in vitro and in vivo experiments, we reveal a novel long noncoding (lncing) driver at chr12p13.3, in which a novel lncRNA GALNT8 Antisense Upstream 1 (GAU1) is initially activated by an open chromatin status, triggering recruitment of the transcription elongation factor TCEA1 at the oncogene GALNT8 promoter and cis-activates the expression of GALNT8. Analysis of The Cancer Genome Atlas (TCGA) clinical database revealed that the GAU1/GALNT8 driver serves as an important indicative biomarker, and targeted silencing of GAU1 via the HKP-encapsulated method exhibited therapeutic efficacy in orthotopic xenografts. Our study presents a novel oncogenetic mechanism in which aberrant tuning of the chromatin state at specific chromosomal loci exposes factor-binding sites, leading to recruitment of trans-factor and activation of oncogenetic driver, thereby provide a novel alternative concept of chromatin dynamics in tumorigenesis.

Jiang W, Cheng Y, Zhao N, et al.
Sulfated polysaccharide of Sepiella Maindroni ink inhibits the migration, invasion and matrix metalloproteinase-2 expression through suppressing EGFR-mediated p38/MAPK and PI3K/Akt/mTOR signaling pathways in SKOV-3 cells.
Int J Biol Macromol. 2018; 107(Pt A):349-362 [PubMed] Related Publications
Previous studies demonstrated that SIP-SII, a sulfated derivative of SIP that is isolated from the ink of Sepiella maindroni, showed significant inhibition of tumor growth and metastasis. In this study, the effects of SIP-SII on the migration, invasion and molecular mechanism in ovarian cancer cell line, SKOV-3 cells, were investigated. The flow cytometry, confocal microscope observation, western blot and RT-PCR results indicated that SIP-SII located on cell membrane and inhibited the expression and activation of epidermal growth factor receptor (EGFR). Moreover, the binding capacity of SIP-SII with EGFR was confirmed by surface plasmon resonance (SPR) analysis and co-localization of EGFR and SIP-SII. Accordingly, SIP-SII was proved to attenuate the EGF-induced EGFR phosphorylation and migration by western blot and wound healing assay, respectively. Additionally, SIP-SII inhibited p38/MAPK and PI3K/Akt/mTOR signaling pathways in SKOV-3 cells significantly. What is more, SIP-SII showed amplified inhibitory activity on migration, invasion, and MMP-2 expression in combination with p38-specific inhibitor, PI3K-specific inhibitor or mTOR-specific inhibitor in SKOV-3 cells. Therefore, the mechanism that SIP-SII suppressed EGFR-mediated p38/MAPK and PI3K/Akt/mTOR signaling pathways to inhibit migration and invasion of SKOV-3 cells was demonstrated. These findings suggested that SIP-SII might be used as a potential inhibitor against tumor metastasis.

Cleaver JE
Transcription coupled repair deficiency protects against human mutagenesis and carcinogenesis: Personal Reflections on the 50th anniversary of the discovery of xeroderma pigmentosum.
DNA Repair (Amst). 2017; 58:21-28 [PubMed] Related Publications
Xeroderma pigmentosum (XP) patients who lack the main damage recognition protein for global genome repair (GGR), XPC, have greatly increased skin cancer rates and elevated mutation frequencies originating from unrepaired ultraviolet photoproducts in the nontranscribed regions of the genome and in nontranscribed strands of expressed genes. But they show no increased mutations in transcribed strands. In contrast, cancer is absent from Cockayne syndrome (CS) patients that have defective transcription coupled repair (TCR) despite severe photosensitivity, CS patients remarkably show no elevation of UV induced mutagenesis implying that defective TCR may be protective against mutagenesis and carcinogenesis. Mutation avoidance in CS is postulated to occur through arrested transcription that generates a tripled stranded R loop consisting of DNA double strands and a nascent mRNA strand. R loops result in S phase apoptosis or activation of ATM kinase that causes a delay in DNA replication until TCR, or transcript cleavage by TFIIS or RNAaseH, relieves the transcription block. Resumption of replication then occurs on repaired DNA without concomitant mutagenesis.

Jiang W, Tian W, Ijaz M, Wang F
Inhibition of EGF-induced migration and invasion by sulfated polysaccharide of Sepiella maindroni ink via the suppression of EGFR/Akt/p38 MAPK/MMP-2 signaling pathway in KB cells.
Biomed Pharmacother. 2017; 95:95-102 [PubMed] Related Publications
SIP-SII, the sulfated Sepiella maindroni ink polysaccharide (SIP), has been manifested to possess anti-tumor and anti-metastasis activity in vivo and in vitro. In the present study, we evaluated its inhibitory effect on the epidermal growth factor (EGF)-induced migration and invasion of human epidermoid carcinoma cell (KB cell line) as well as the related signaling pathways. The results of MTT assay indicated that SIP-SII inhibited the proliferation of KB cells in a concentration and time dependent manner. Notably, the attenuation of cell growth by SIP-SII was enlarged in the presence of EGF. The wound healing assay and transwell invasion assay were used to evaluate the effect of SIP-SII on the EGF-induced migration and invasion of KB cells and the results showed that SIP-SII markedly attenuated the EGF-induced migration and invasion. Besides, the EGF-induced matrix metalloproteinase-2 (MMP-2) expression was also suppressed by SIP-SII. However, SIP-SII showed no significant inhibition of the EGF-induced matrix metalloproteinase-9 (MMP-9) expression. Further research revealed that SIP-SII decreased the EGF-induced phosphorylation of epidermal growth factor receptor (EGFR), Akt and p38, but no significant suppression on EGF-induced phosphorylation of extracellular signal-regulated kinase 1 and 2 (Erk1/2) and c-Jun N-terminal kinases (JNK) by SIP-SII treatment was observed. The involvement of EGFR/Akt/p38 pathway was confirmed by evidence that SIP-SII would enlarge the inhibitory effect of the specific signal pathway inhibitors. These results indicate that SIP-SII has the potential to be used as the inhibitor of tumor metastasis especially for cancers characterized by over-activation of EGF/EGFR signaling.

Franco-Salla GB, Prates J, Cardin LT, et al.
Euphorbia tirucalli modulates gene expression in larynx squamous cell carcinoma.
BMC Complement Altern Med. 2016; 16:136 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Some plants had been used in the treatment of cancer and one of these has attracted scientific interest, the Euphorbia tirucalli (E. tirucalli), used in the treatment of asthma, ulcers, warts has active components with activities scientifically proven as antimutagenic, anti-inflammatory and anticancer.
METHODS: We evaluate the influence of the antitumoral fraction of the E. tirucalli latex in the larynx squamous cell carcinoma (Hep-2), on the morphology, cell proliferation and gene expression. The Hep-2 cells were cultivated in complete medium (MEM 10 %) and treated with E. tirucalli latex for 1, 3, 5 and 7 days. After statistically analyzing the proliferation of the tested cells, the cells were cultivated again for RNA extraction and the Rapid Subtractive Hybridization (RaSH) technique was used to identify genes with altered expression. The genes found using the RaSH technique were analyzed by Gene Ontology (GO) using Ingenuity Systems.
RESULTS: The five genes found to have differential expression were validated by real-time quantitative PCR. Though treatment with E. tirucalli latex did not change the cell morphology in comparison to control samples, but the cell growth was significantly decreased. The RaSH showed change in the expression of some genes, including ANXA1, TCEA1, NGFRAP1, ITPR1 and CD55, which are associated with inflammatory response, transcriptional regulation, apoptosis, calcium ion transport regulation and complement system, respectively. The E. tirucalli latex treatment down-regulated ITPR1 and up-regulated ANXA1 and CD55 genes, and was validated by real-time quantitative PCR.
CONCLUSIONS: The data indicate the involvement of E. tirucalli latex in the altered expression of genes involved in tumorigenic processes, which could potentially be applied as a therapeutic indicator of larynx cancer.

Liao JM, Cao B, Deng J, et al.
TFIIS.h, a new target of p53, regulates transcription efficiency of pro-apoptotic bax gene.
Sci Rep. 2016; 6:23542 [PubMed] Free Access to Full Article Related Publications
Tumor suppressor p53 transcriptionally regulates hundreds of genes involved in various cellular functions. However, the detailed mechanisms underlying the selection of p53 targets in response to different stresses are still elusive. Here, we identify TFIIS.h, a transcription elongation factor, as a new transcriptional target of p53, and also show that it can enhance the efficiency of transcription elongation of apoptosis-associated bax gene, but not cell cycle-associated p21 (CDKN1A) gene. TFIIS.h is revealed as a p53 target through microarray analysis of RNAs extracted from cells treated with or without inauhzin (INZ), a p53 activator, and further confirmed by RT-q-PCR, western blot, luciferase reporter, and ChIP assays. Interestingly, knocking down TFIIS.h impairs, but overexpressing TFIIS.h promotes, induction of bax, but not other p53 targets including p21, by p53 activation. In addition, overexpression of TFIIS.h induces cell death in a bax- dependent fashion. These findings reveal a mechanism by which p53 utilizes TFIIS.h to selectively promote the transcriptional elongation of the bax gene, upsurging cell death in response to severe DNA damage.

Li J, Zheng Q, Peng L, Huang Z
Survival impact index and ultrahigh-dimensional model-free screening with survival outcomes.
Biometrics. 2016; 72(4):1145-1154 [PubMed] Free Access to Full Article Related Publications
Motivated by ultrahigh-dimensional biomarkers screening studies, we propose a model-free screening approach tailored to censored lifetime outcomes. Our proposal is built upon the introduction of a new measure, survival impact index (SII). By its design, SII sensibly captures the overall influence of a covariate on the outcome distribution, and can be estimated with familiar nonparametric procedures that do not require smoothing and are readily adaptable to handle lifetime outcomes under various censoring and truncation mechanisms. We provide large sample distributional results that facilitate the inference on SII in classical multivariate settings. More importantly, we investigate SII as an effective screener for ultrahigh-dimensional data, not relying on rigid regression model assumptions for real applications. We establish the sure screening property of the proposed SII-based screener. Extensive numerical studies are carried out to assess the performance of our method compared with other existing screening methods. A lung cancer microarray data is analyzed to demonstrate the practical utility of our proposals.

Li J, Jin Y, Pan S, et al.
TCEA3 Attenuates Gastric Cancer Growth by Apoptosis Induction.
Med Sci Monit. 2015; 21:3241-6 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The aim of this study was to investigate and interpret the expression level and potential function of TCEA3 in gastric cancer.
MATERIAL AND METHODS: qRT-PCR was used to determine the expression level of TCEA3 in gastric cancer tissues. Pearson χ2 test was performed to clarify the correlation between TCEA3 expression and patients' clinicopathologic characteristics. Biological function of TCEA3 was tested by proliferation assay and colony formation assay. Flow cytometry was used to study the potential function of TCEA3 in apoptosis induction.
RESULTS: TCEA3 expression was significantly downregulated in gastric cancer tissues compared with paired normal tissues. Poor prognoses were observed in the low TCEA3 expression group of patients in contrast to the high TCEA3 expression group. Functionally, upregulation of TCEA3 inhibited gastric cancer cell proliferation and colony formation. We also found that TCEA3 may attenuate cell growth through apoptosis induction.
CONCLUSIONS: Our findings suggest that TCEA3 attenuates the proliferation and induces apoptosis of gastric cancer cells.

Zali H, Rezaei Tavirani M
Meningioma protein-protein interaction network.
Arch Iran Med. 2014; 17(4):262-72 [PubMed] Related Publications
BACKGROUND: Meningioma is one of the most common central nervous system tumors that derived from meningothelial (arachnoid cap) cells. This paper identified the network-based Protein-Protein Interactions (PPI) for meningioma relative to healthy control.
METHODS: Gene expression data including 384 gene or protein names extracted from a number of beforehand investigations.
RESULTS: Out of these 384 proteins, 176 were found to be exclusively expressed in meningiomas and 208 proteins were down-regulated. The networks of related differentially expressed genes were explored using cytoscape and the PPI analysis methods such as MCODE and ClueGO. Results analysis introduced a number of hub proteins and 27 clusters (protein complex) with distinctive seed genes. Identified ClueGO Pathways based on subnetworks mined by MCODE composed of positive regulation in RBC homeostasis, dysregulation of transport from ER to Golgi, disruption regulation of cell cycle and antigen processing and presentation of exogenous peptide antigen and neutralization of exogenous dsRNA. Combination of over expression of TCEA1, UBE2E1, XRCC5, IFIT1, IFIT-3, MCM2, and MCM7 and under expression of CDC25A, SEC31A, and CDK6 can serve as diagnostic biomarker panel for meningiomas.
CONCLUSION: These introduced network-based biomarkers for the meningioma patterns may be helpful in diagnosis, prognosis and treatment processes however biomarker validation is necessary.

Huang CY, Chen YM, Zhao JJ, et al.
Decreased expression of transcription elongation factor A-like 7 is associated with gastric adenocarcinoma prognosis.
PLoS One. 2013; 8(1):e54671 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: We sought to investigate the expression levels and prognosis value of TCEAL7 in primary gastric cancer.
METHODS AND RESULTS: We investigated TCEAL7 and other homologous five members of the TCEAL family expression in normal gastricepithelial cell line and gastric cancer cell lines using real-time quantitative PCR. Furthermore, we examined the expression of TCEAL7 in 39 paired cancerous and matched adjacent noncancerous gastric mucosa tissues by real-time quantitative PCR and western blotting. Moreover, we analyzed TCEAL7 expression in 406 gastric cancer patients using immunohistochemistry. The relationships between the TCEAL7 expression levels, the clinicopathological factors, and patient survival were investigated. RT- qPCR data showed that mRNA expression level of TCEAL7 was significantly lower in the gastric cancer cell lines comparing with the levels of other five members of the TCEAL family. Results also revealed decreased TCEAL7 mRNA (P = 0.025) and protein (P = 0.012) expression in tumor tissue samples compared with matched adjacent non-tumor tissue samples. Immunohistochemical staining data showed that TCEAL7 expression was significantly decreased in 43.3% of gastric adenocarcinoma cases. The result also showed that the low TCEAL7 expression was significantly correlated with female, larger tumor size, higher histological grade and worse nodal status. Kaplan-Meier survival curves revealed that the reduced expression of TCEAL7 was associated with a poor prognosis in gastric adenocarcinoma patients (P<0.001). Based on a univariate analysis that included all 406 patients, TCEAL7 expression was found to have statistically significant associations with overall survival (P<0.001). Multivariate analysis also demonstrated that TCEAL7 expression (P = 0.009), age, tumor size, histological grade, lymphovascular invasion, T stage, N stage and M stage were independent risk factors in the prognosis of gastric cancer patients.
CONCLUSIONS: Our study suggests that TCEAL7 might serve as a candidate tumor suppressor and a potential prognostic biomarker in gastric carcinogenesis.

Zong A, Zhao T, Zhang Y, et al.
Anti-metastatic and anti-angiogenic activities of sulfated polysaccharide of Sepiella maindroni ink.
Carbohydr Polym. 2013; 91(1):403-9 [PubMed] Related Publications
A previous study demonstrated that SIP-SII, a sulfated Sepiella maindroni ink polysaccharide, suppressed the invasion and migration of cancer cells via the inhibition of the proteolytic activity of matrix metalloproteinase-2 (MMP-2). Therefore, this study investigated the anti-metastatic effect of SIP-SII in vivo. SIP-SII (15 and 30 mg/kg d) markedly decreased B16F10 pulmonary metastasis in mice models by 85.9% and 88.0%, respectively. Immunohistochemistry showed that SIP-SII decreased the expression of the intercellular adhesion molecule 1 (ICAM-1) and basic fibroblast growth factor (bFGF) in lung metastasis nodules. In addition, SIP-SII inhibited neovascularization in chick chorioallantoic membrane assay at 0.08-2 mg/mL. In the in vitro experiments, SIP-SII (0.8-500 μg/mL) significantly decreased the protein and mRNA expression of ICAM-1 and bFGF in SKOV3 and EA.hy926 cells, respectively. These results suggested that SIP-SII might suppress melanoma metastasis via the inhibition of the tumor adhesion mediated by ICAM-1 and the angiogenesis mediated by bFGF, as well as resulting in depression of the invasion and migration of carcinoma cells.

Matsuyama A, Hisaoka M, Hashimoto H
PLAG1 expression in cutaneous mixed tumors: an immunohistochemical and molecular genetic study.
Virchows Arch. 2011; 459(5):539-45 [PubMed] Related Publications
Cutaneous mixed tumors, also known as chondroid syringomas, are benign cutaneous adnexal tumors that exhibit remarkable histopathological similarities to pleomorphic adenoma of the salivary gland. Thus far, there is little information on the genetic profiles of cutaneous mixed tumors, although specific genetic aberrations including fusion genes involving PLAG1 and HMGA2 have been demonstrated in pleomorphic adenomas. In the present study, we conducted an immunohistochemical evaluation of PLAG1 and a reverse transcription-polymerase chain reaction (RT-PCR) assay to detect fusion gene transcripts associated with pleomorphic adenoma, including the CTNNB1-PLAG1, LIFR-PLAG1, CHCHD7-PLAG1, TCEA1-PLAG1, HMGA2-FHIT, HMGA2-NFIB, and HMGA2-WIF1 fusion transcripts; this was performed using formalin-fixed paraffin-embedded tumor tissue specimens of 16 cutaneous mixed tumors including one sample with an adenocarcinoma component. All 16 cutaneous mixed tumors were immunoreactive to PLAG1, which was predominantly expressed in cells with myoepithelial or chondroid differentiation accounting for >80% of cells, whereas PLAG1 expression in glandular or squamous tumor cells was restricted to <20% of cells. The carcinoma component in the mixed tumor was also positive for PLAG1. On the other hand, all eight cutaneous adnexal tumors other than the mixed tumor were negative for PLAG1. In RT-PCR analysis, no fusion gene transcripts involving PLAG1 or HMGA2 were identified in any of the cases. Concordant with previous studies, our results support the close relationship between cutaneous mixed tumors and pleomorphic adenomas of the salivary gland. However, the mechanism of PLAG1 expression in cutaneous mixed tumors appears to be possibly different from that of pleomorphic adenomas.

Shema E, Kim J, Roeder RG, Oren M
RNF20 inhibits TFIIS-facilitated transcriptional elongation to suppress pro-oncogenic gene expression.
Mol Cell. 2011; 42(4):477-88 [PubMed] Free Access to Full Article Related Publications
hBRE1/RNF20 is the major E3 ubiquitin ligase for histone H2B. RNF20 depletion causes a global reduction of monoubiquitylated H2B (H2Bub) levels and augments the expression of growth-promoting, pro-oncogenic genes. Those genes reside preferentially in compact chromatin and are inefficiently transcribed under basal conditions. We now report that RNF20, presumably via H2Bub, selectively represses those genes by interfering with chromatin recruitment of TFIIS, a factor capable of relieving stalled RNA polymerase II. RNF20 inhibits the interaction between TFIIS and the PAF1 complex and hinders transcriptional elongation. TFIIS ablation selectively abolishes the upregulation of those genes upon RNF20 depletion and attenuates the cellular response to EGF. Consistent with its positive role in transcription of pro-oncogenic genes, TFIIS expression is elevated in various human tumors. Our findings provide a molecular mechanism for selective gene repression by RNF20 and position TFIIS as a key target of RNF20's tumor suppressor activity.

Matsuyama A, Hisaoka M, Nagao Y, Hashimoto H
Aberrant PLAG1 expression in pleomorphic adenomas of the salivary gland: a molecular genetic and immunohistochemical study.
Virchows Arch. 2011; 458(5):583-92 [PubMed] Related Publications
The morphologic distinction of pleomorphic adenoma from other benign or low-grade salivary gland tumors is sometimes difficult and problematic because of their potentially overlapping histological patterns. A subset of pleomorphic adenoma harbors specific gene alterations involving PLAG1 or HMGA2, and the detection of these fusion genes and their products using formalin-fixed, paraffin-embedded (FFPE) tumor specimens may be a useful diagnostic adjunct. In the present study, gene fusions involving PLAG1 or HMGA2 were examined by reverse transcription-polymerase chain reaction (RT-PCR) analysis, with FFPE tumor tissues and immunohistochemical expression of PLAG1 in 45 pleomorphic adenomas, using a commercially available antibody. RT-PCR analyses identified the CTNNB1-PLAG1, LIFR-PLAG1, CHCHD7-PLAG1, and HMGA2-WIF1 fusion transcripts in eight, two, one, and one case, respectively. The TCEA1-PLAG1, HMGA2-FHIT, and HMGA2-NFIB fusion transcripts were not detected. Immunohistochemically, tumor cells in all 45 pleomorphic adenomas were positive for PLAG1, irrespective of PLAG1 rearrangements, even in the case with the HMGA2-WIF1 fusion transcript. Tumor cells displaying myoepithelial or cartilaginous differentiation were almost constantly positive for PLAG1, whereas a limited expression was observed in glandular or keratinizing cells. Among the 46 tumors other than pleomorphic adenoma, 4 carcinomatous components of carcinomas ex pleomorphic adenoma were positive for PLAG1, the other 39 were negative for PLAG1, and the remaining 3 were only faintly and/or focally stained, indicating that the immunohistochemical detection of PLAG1 is diagnostically useful. The present results also suggest that overexpression of PLAG1 is essential for the tumorigenesis of pleomorphic adenomas, although the mechanisms mediating PLAG1 overexpression seem to be variable.

Burcham PC, Raso A, Thompson CA
Toxicity of smoke extracts towards A549 lung cells: role of acrolein and suppression by carbonyl scavengers.
Chem Biol Interact. 2010; 183(3):416-24 [PubMed] Related Publications
The noxious 3-carbon electrophile acrolein forms on combustion of diverse organic matter including synthetic polymers such as polyethylene. While known to play a key role in smoke inhalation injury (SII), the molecular basis for the pulmonary toxicity of high dose acrolein-containing smoke is unclear. As a result, drug interventions in SII are poorly directed against pathogenetic smoke toxicants such as acrolein. The first aim of this study was to confirm a role for acrolein in the acute toxicity of smoke extracts towards A549 lung cells by monitoring adduction of known acrolein targets and the expression of acrolein-inducible genes. A second aim was to evaluate carbonyl scavengers for their abilities to protect cell targets and block smoke extract toxicity. Extracts were prepared by bubbling smoke released by smouldering polyethylene through a buffered saline-trap. Acrolein levels in the extracts were estimated via HPLC after derivatisation with 2,4-dinitrophenylhydrazine. Extracts were highly toxic towards A549 cells, eliciting greater ATP depletion than an equivalent concentration of acrolein alone. The toxicity was accompanied by pronounced carbonylation of several cytoskeletal targets, namely vimentin and keratins-7, -8 and -18. Western blotting revealed that polyethylene combustion products also upregulated several acrolein-responsive protein markers, including GADD45beta, NQO1, HMOX, Hsp70, Nur77 and Egr1. Several carbonyl scavengers (bisulfite, d-penicillamine, hydralazine and 1-hydrazinoisoquinoline) strongly attenuated smoke extract toxicity, with bisulfite suppressing both the adduction and cross-linking of intermediate filament targets. Bisulfite also suppressed the cytotoxicity of smoke extracts when detected using real-time monitoring of cellular impedance. These findings confirm a key role for acrolein in smoke cytotoxicity and suggest drugs that block acrolein toxicity deserve further investigation as possible interventions against SII.

Peedicayil A, Vierkant RA, Shridhar V, et al.
Polymorphisms in TCEAL7 and risk of epithelial ovarian cancer.
Gynecol Oncol. 2009; 114(2):260-4 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: We have previously shown that TCEAL7 (transcription elongation factor A (SII)-like 7) is epigenetically down-regulated in the majority of epithelial ovarian cancers. We now examine the hypothesis that inherited alterations in TCEAL7 play a role in the etiology of ovarian cancer.
METHODS: A two-site case-control study of 930 cases of ovarian cancer and 1037 controls, frequency-matched on residence, age and race, was conducted. Six informative SNPs (tagSNPs and putative-functional SNPs) were genotyped. Logistic regression was used to adjust for potential confounders and determine if inherited variation at this locus was associated with risk of ovarian cancer in general and among cases with invasive disease and serous histology. Gene-level principal component and haplotype analyses were also conducted.
RESULTS: None of the SNPs or haplotypes studied were significantly associated with ovarian cancer risk overall. However, among the 440 invasive serous cases, the minor alleles for three correlated SNPs were significantly associated with reduced risk (p-values<0.05), summarized gene-level variation was weakly associated with reduced risk (p-value=0.05), and the predominant haplotype was less common among cases than controls (0.36 v 0.40, p-value=0.05), consistent with single-SNP results.
CONCLUSION: TCEAL7 polymorphisms may play a role in the development of invasive serous ovarian cancers. Follow-up molecular and replication studies are warranted.

Hubbard K, Catalano J, Puri RK, Gnatt A
Knockdown of TFIIS by RNA silencing inhibits cancer cell proliferation and induces apoptosis.
BMC Cancer. 2008; 8:133 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: A common element among cancer cells is the presence of improperly controlled transcription. In these cells, the degree of specific activation of some genes is abnormal, and altering the aberrant transcription may therefore directly target cancer. TFIIS is a transcription elongation factor, which directly binds the transcription motor, RNA Polymerase II and allows it to read through various transcription arrest sites. We report on RNA interference of TFIIS, a transcription elongation factor, and its affect on proliferation of cancer cells in culture.
METHODS: RNA interference was performed by transfecting siRNA to specifically knock down TFIIS expression in MCF7, MCF10A, PL45 and A549 cells. Levels of TFIIS expression were determined by the Quantigene method, and relative protein levels of TFIIS, c-myc and p53 were determined by C-ELISA. Induction of apoptosis was determined by an enzymatic Caspase 3/7 assay, as well as a non-enzymatic assay detecting cytoplasmic mono- and oligonucleosomes. A gene array analysis was conducted for effects of TFIIS siRNA on MCF7 and MCF10A cell lines.
RESULTS: Knockdown of TFIIS reduced cancer cell proliferation in breast, lung and pancreatic cancer cell lines. More specifically, TFIIS knockdown in the MCF7 breast cancer cell line induced cancer cell death and increased c-myc and p53 expression whereas TFIIS knockdown in the non-cancerous breast cell line MCF10A was less affected. Differential effects of TFIIS knockdown in MCF7 and MCF10A cells included the estrogenic, c-myc and p53 pathways, as observed by C-ELISA and gene array, and were likely involved in MCF7 cell-death.
CONCLUSION: Although transcription is a fundamental process, targeting select core transcription factors may provide for a new and potent avenue for cancer therapeutics. In the present study, knockdown of TFIIS inhibited cancer cell proliferation, suggesting that TFIIS could be studied as a potential cancer target within the transcription machinery.

Tan BK, Tan LK, Yu K, et al.
Clinical validation of a customized multiple signature microarray for breast cancer.
Clin Cancer Res. 2008; 14(2):461-9 [PubMed] Related Publications
PURPOSE: Current histopathologic systems for classifying breast tumors require evaluation of multiple variables and are often associated with significant interobserver variability. Recent studies suggest that gene expression profiles may represent a promising alternative for clinical cancer classification. Here, we investigated the use of a customized microarray as a potential tool for clinical practice.
EXPERIMENTAL DESIGN: We fabricated custom 188-gene microarrays containing expression signatures for three breast cancer molecular subtypes [luminal/estrogen receptor (ER) positive, human epidermal growth factor receptor 2 (HER2), and "basaloid"], the Nottingham prognostic index (NPI-ES), and low histologic grade (TuM1). The reliability of these multiple-signature arrays (MSA) was tested in a prospective cohort of 165 patients with primary breast cancer.
RESULTS: The MSA-ER signature exhibited a high concordance of 90% with ER immunohistochemistry reported on diagnosis (P < 0.001). This remained unchanged at 89% (P < 0.001) when the immunohistochemistry was repeated using current laboratory standards. Expression of the HER2 signature showed a good correlation of 76% with HER2 fluorescence in situ hybridization (FISH; ratio > or =2.2; P < 0.001), which further improved to 89% when the ratio cutoff was raised to > or =5. A proportion of low-level FISH-amplified samples (ratio, 2.2-5) behaved comparably to FISH-negative samples by HER2 signature expression, HER2 quantitative reverse transcription-PCR, and HER2 immunohistochemistry. Luminal/ER+ tumors with high NPI-ES expression were associated with high NPI scores (P = 0.001), and luminal/ER+ TuM1-expressing tumors were significantly correlated with low histologic grade (P = 0.002) and improved survival outcome in an interim analysis (hazard ratio, 0.2; P = 0.019).
CONCLUSION: The consistency of the MSA platform in an independent patient population suggests that custom microarrays could potentially function as an adjunct to standard immunohistochemistry and FISH in clinical practice.

Selvarajan S, Sii LH, Lee A, et al.
Parafibromin expression in breast cancer: a novel marker for prognostication?
J Clin Pathol. 2008; 61(1):64-7 [PubMed] Related Publications
BACKGROUND: Parafibromin is a novel protein product of HRPT2, a recently identified tumour suppressor gene. Mutations of the HRPT2 gene are common in parathyroid carcinomas, and these exhibit reduced protein expression. Parafibromin expression in breast cancer has not been previously studied.
AIMS: To determine the distribution of parafibromin in breast cancer tissues, and correlate its expression with conventional pathological parameters.
METHODS: Tissue microarrays were constructed from archival paraffin embedded breast cancer samples. Sections cut from tissue microarray blocks were subjected to immunohistochemistry. Immunopositivity for parafibromin and intensity-percentage scores were derived by blinded evaluation. Findings were correlated with clinicopathological parameters.
RESULTS: 163 breast cancers were assessed. Larger tumours were less likely to express parafibromin than smaller ones, with the association approaching statistical significance (p = 0.05). Staining intensity correlated inversely with tumour size (p = 0.016) and pathological stage (p = 0.008); as did parafibromin intensity-percentage score with pathological stage (p = 0.03), lymphovascular invasion (p = 0.03) and cerbB2 intensity-percentage score (p = 0.04).
CONCLUSION: Parafibromin in breast cancer, as in parathyroid tumours, appears to have tumour suppressor functions, with loss of protein expression associated with adverse pathological parameters. These findings may indicate a potential role of parafibromin as a prognostic marker in breast cancer.

Desmond JC, Raynaud S, Tung E, et al.
Discovery of epigenetically silenced genes in acute myeloid leukemias.
Leukemia. 2007; 21(5):1026-34 [PubMed] Related Publications
The demethylating 5-aza-2'deoxycytidine (DAC) and the histone deacetylase inhibitor (HDACi) suberoyl anilide bishydroxamide (SAHA) possess potent antitumorigenic properties in myeloid disorders. However, the transcriptome alterations mediated by these drugs are poorly understood. We analyzed the transcriptional effects of DAC and SAHA in the AML cell line KG-1. Microarray analyses revealed 76 genes expressed in normal CD34+ cells, absent in KG-1 cells but whose expression was induced after drug treatment. A total of 39 of these genes harbored CpG islands in their promoters. We examined the expression level of these genes in 120 AML patient samples representing diverse karyotpyes. Gas2l1, tfIIs, ehd3, enolase 2, mx1, dral, astml and pxdn were diminished across all AML karyotypes examined. Ehd3 was methylated in 63% of AML patients examined. This methylation was lost upon complete remission, and not observed in normal CD34+ cells. CD34+ cells expressed ehd3 at approximately 10-fold higher levels than AML samples. Another highlighted gene, alpha-catenin, is located at q31 of chromosome 5. Analyses of 29 5q- AML/myelodysplastic syndrome (MDS) samples revealed marked decreases in expression of alpha-catenin, compared to non-5q- MDS samples (6.6+/-9-fold). However, no methylation was detected, suggesting indirect effects of these drugs on the expression of alpha-catenin.

Liu Z, Zhou Z, Chen G, Bao S
A putative transcriptional elongation factor hIws1 is essential for mammalian cell proliferation.
Biochem Biophys Res Commun. 2007; 353(1):47-53 [PubMed] Related Publications
Iws1 has been implicated in transcriptional elongation by interaction with RNA polymerase II (RNAP II) and elongation factor Spt6 in budding yeast Saccharomyces cerevisiae, and association with transcription factor TFIIS in mammalian cells, but its role in controlling cell growth and proliferation remains unknown. Here we report that the human homolog of Iws1, hIws1, physically interacts with protein arginine methyltransferases PRMT5 which methylates elongation factor Spt5 and regulates its interaction with RNA polymerase II. Gene-specific silencing of hIws1 by RNA interference reveals that hIws1 is essential for cell viability. GFP fusion protein expression approaches demonstrate that the hIws1 protein is located in the nucleus, subsequently, two regions harbored within the hIws1 protein are demonstrated to contain nuclear localization signals (NLSs). In addition, mouse homolog of hiws1 is found to express ubiquitously in various tissues.

Chen W, Salto-Tellez M, Palanisamy N, et al.
Targets of genome copy number reduction in primary breast cancers identified by integrative genomics.
Genes Chromosomes Cancer. 2007; 46(3):288-301 [PubMed] Related Publications
The identification of specific oncogenes and tumor suppressor genes in regions of recurrent aneuploidy is a major challenge of molecular cancer research. Using both oligonucleotide single-nucleotide polymorphism and mRNA expression arrays, we integrated genomic and transcriptional information to identify and prioritize candidate cancer genes in regions of increased and decreased chromosomal copy number in a cohort of primary breast cancers. Confirming the validity of this approach, several regions of previously-known copy number (CN) alterations in breast cancer could be successfully reidentified. Focusing on regions of decreased CN, we defined a prioritized list of eighteen candidate genes, which included ARPIN, FBN1, and LZTS1, previously shown to be associated with cancers in breast or other tissue types, and novel genes such as P29, MORF4L1, and TBC1D5. One such gene, the RUNX3 transcription factor, was selected for further study. We show that RUNX3 is present at reduced CNs in proportion to the rest of the tumor genome and that RUNX3 CN reductions can also be observed in a breast cancer series from a different center. Using tissue microarrays, we demonstrate in an independent cohort of over 120 breast tissues that RUNX3 protein is expressed in normal breast epithelium but not fat and stromal tissue, and widely down-regulated in the majority of breast cancers (>85%). In vitro, RUNX3 overexpression suppressed the invasive potential of MDA-MB-231 breast cancer cells in a matrigel assay. Our results demonstrate the utility of integrative genomic approaches to identify novel potential cancer-related genes in primary tumors. This article contains Supplementary Material available at

Akaishi J, Onda M, Okamoto J, et al.
Down-regulation of transcription elogation factor A (SII) like 4 (TCEAL4) in anaplastic thyroid cancer.
BMC Cancer. 2006; 6:260 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies and appears to arise mainly from transformation of pre-existing differentiated thyroid cancer (DTC). However, the carcinogenic mechanism of anaplastic transformation remains unclear. Previously, we investigated specific genes related to ATC based on gene expression profiling using cDNA microarray analysis. One of these genes, transcription elongation factor A (SII)-like 4 (TCEAL4), encodes a member of the transcription elongation factor A (SII)-like gene family. The detailed function of TCEAL4 has not been described nor has any association between this gene and human cancers been reported previously.
METHODS: To investigate the role of TCEAL4 in ATC carcinogenesis, we examined expression levels of TCEAL4 in ACLs as well as in other types of thyroid cancers and normal human tissue.
RESULTS: Expression of TCEAL4 was down-regulated in all 11 ACLs as compared to either normal thyroid tissues or papillary and follicular thyroid cancerous tissues. TCEAL4 was expressed ubiquitously in all normal human tissues tested.
CONCLUSION: To our knowledge, this is the first report of altered TCEAL4 expression in human cancers. We suggest that loss of TCEAL4 expression might be associated with development of ATC from DTC. Further functional studies are required.

Selvarajan S, Tan SY, Sii LH, Tan PH
c-erbB-2 (HER-2/neu) immunohistochemistry in invasive breast cancer: is there concordance between standard sections and tissue microarrays?
Pathology. 2006; 38(4):316-20 [PubMed] Related Publications
AIMS: Immunohistochemical detection of the 185-kDa transmembrane glycoprotein product of the proto-oncogene c-erbB-2 (also known as HER-2/neu), located on chromosome 17q21, is a well established method of evaluation in invasive breast cancer. This investigation is currently performed on standard sections cut from the tumour containing paraffin block. It is uncertain if concordant results can be obtained on tissue microarray (TMA) sections, a high throughput technique that is particularly advantageous in research and validation protocols. Our aim in this study was to compare the results of c-erbB-2 immunoexpression in standard sections of invasive breast cancers with those of TMAs.
METHODS: Standard sections and TMAs constructed from archival paraffin-embedded breast cancers of 184 patients who had surgery in Singapore General Hospital during the period 1998-2002 were subjected to immunohistochemistry using the commercial antibody (A0485, Dako). c-erbB-2 over-expression was evaluated according to cytoplasmic membrane staining intensity, which was defined as 2+ and 3+ staining.
RESULTS: Over-expression of c-erbB-2 protein was found in 21.2% (39/184) and 18.6% (34/183) of cases on standard sections and TMAs, respectively. There was substantial agreement between these two types of sections (k = 0.724) when positive and negative staining was considered.
CONCLUSION: Immunohistochemistry on TMAs for c-erbB-2 expression in breast cancer is a reliable alternative to that performed on routine standard sections, as it is both cost effective and time efficient, especially in a research setting.

Asp J, Persson F, Kost-Alimova M, Stenman G
CHCHD7-PLAG1 and TCEA1-PLAG1 gene fusions resulting from cryptic, intrachromosomal 8q rearrangements in pleomorphic salivary gland adenomas.
Genes Chromosomes Cancer. 2006; 45(9):820-8 [PubMed] Related Publications
Pleomorphic salivary gland adenomas are characterized by recurrent chromosome rearrangements of 8q12, leading to activation of the PLAG1 oncogene. Here we demonstrate that CHCHD7-PLAG1 is a novel and recurrent gene fusion generated by a cytogenetically cryptic rearrangement in pleomorphic adenomas. CHCHD7 is a newly identified member of a multifamily of proteins containing a conserved (coiled coil 1)-(helix 1)-(coiled coil 2)-(helix 2) domain. Northern blot analysis revealed that the gene is ubiquitously expressed. Its biological function is unknown and the gene has hitherto not been associated with neoplasia. CHCHD7 and PLAG1 are located head-to-head about 500 bp apart in 8q12. Molecular analyses of 27 tumors revealed CHCHD7-PLAG1 fusions in three tumors, two of which had t(6;8) and t(8;15) translocations as the sole anomalies and one a normal karyotype. FISH analyses of interphase nuclei and nuclear chromatin fibers of a fourth adenoma with a normal karyotype revealed that a second fusion partner gene, TCEA1, located about 2 Mb centromeric to PLAG1, also is fused to PLAG1 as a result of a cryptic 8q rearrangement. The breakpoints in both fusions occur in the 5'-noncoding regions of the genes, leading to activation of PLAG1 by promoter swapping/substitution. Western blot and immunohistochemical analyses demonstrated that the PLAG1 protein was overexpressed in epithelial, myoepithelial, and mesenchymal-like tumor cells in tumors with both fusions. Our findings further emphasize the significance of PLAG1 activation in pleomorphic adenomas and demonstrate that the gene is more frequently activated than previously anticipated.

Fischer U, Struss AK, Hemmer D, et al.
PHF3 expression is frequently reduced in glioma.
Cytogenet Cell Genet. 2001; 94(3-4):131-6 [PubMed] Related Publications
Glioblastoma is the most frequent brain tumor and accounts for approximately 50--60% of all astrocytic tumors. Many chromosome alterations have been described in glioblastoma, but only for a few alterations were the genes identified and linked to genetic pathways in glioblastoma development. To contribute to the identification of novel genes involved in glioblastoma development we used a combined immunological and molecular screening approach. Here we report the identification and expression analysis of a novel gene from human chromosome 6q12 that is considered to be the third member of a family of PHD finger containing genes and is termed PHF3. PHF3 is ubiquitously expressed in normal tissues including brain, but its expression is significantly reduced or lost in glioblastoma, glioblastoma cell lines, anaplastic astrocytomas and astrocytomas. The PHF3 protein sequence contains several protein motifs frequently found in transcription factors. One of those motifs is a PHD finger, also termed LAP motif and known to bind large portions of DNA. Another region of the protein revealed a high homology to the transcription factor TFIIS, especially to a region that is necessary for the Polymerase II binding properties of TFIIS. Combining these results, PHF3 is a novel member of a large class of regulatory proteins containing a LAP motif, and loss of its expression in glioblastoma may contribute to glioma development.

Struss AK, Romeike BF, Munnia A, et al.
PHF3-specific antibody responses in over 60% of patients with glioblastoma multiforme.
Oncogene. 2001; 20(31):4107-14 [PubMed] Related Publications
Glioblastoma multiforme (GBM), a malignant astrocytic tumour, represents the most frequent tumour of the human brain. Nevertheless, its molecular pathology is not well understood. We utilized the immune system, which contributes to cancer protection, to help identify new GBM-related genes. By screening a human GBM cDNA library with autologous patient serum (SEREX-approach), we isolated a gene termed PHF3 (PHD finger protein 3). The gene product of PHF3 is immunogenic in GBM as tested in an allogenic patient serum screening demonstrating antibodies in 24 of 39 (61.53%) sera, whereas none of the 14 healthy persons had antibodies against PHF3. While previous SEREX studies revealed allogenic antibody responses up to 40%, our results for PHF3 represent the highest reported rate for a specific antibody response. We show that GBM patients with an antibody response against PHF3 show significant better survival than patients without PHF3-specific antibodies. Because the amino acid sequence of PHF3 contains a PHD finger (also termed LAP motif), a TFIIS homology, a proline rich region and nuclear localization signals, it supposedly functions as a transcription factor. A polyclonal antibody generated against PHF3 shows nuclear expression in most investigated formalin-fixed, paraffin embedded tissues. In GBM, PHF3 expression is concentrated in cells surrounding necroses.

Aström AK, Voz ML, Kas K, et al.
Conserved mechanism of PLAG1 activation in salivary gland tumors with and without chromosome 8q12 abnormalities: identification of SII as a new fusion partner gene.
Cancer Res. 1999; 59(4):918-23 [PubMed] Related Publications
We have previously shown (K. Kas et al, Nat. Genet., 15: 170-174, 1997) that the developmentally regulated zinc finger gene pleomorphic adenoma gene 1 (PLAG1) is the target gene in 8q12 in pleomorphic adenomas of the salivary glands with t(3;8)(p21;q12) translocations. The t(3;8) results in promoter swapping between PLAG1 and the constitutively expressed gene for beta-catenin (CTNNB1), leading to activation of PLAG1 expression and reduced expression of CTNNB1. Here we have studied the expression of PLAG1 by Northern blot analysis in 47 primary benign and malignant human tumors with or without cytogenetic abnormalities of 8q12. Overexpression of PLAG1 was found in 23 tumors (49%). Thirteen of 17 pleomorphic adenomas with a normal karyotype and 5 of 10 with 12q13-15 abnormalities overexpressed PLAG1, which demonstrates that PLAG1 activation is a frequent event in adenomas irrespective of karyotype. In contrast, PLAG1 was overexpressed in only 2 of 11 malignant salivary gland tumors analyzed, which suggests that, at least in salivary gland tumors, PLAG1 activation preferentially occurs in benign tumors. PLAG1 over-expression was also found in three of nine mesenchymal tumors, i.e., in two uterine leiomyomas and one leiomyosarcoma. RNase protection, rapid amplification of 5'-cDNA ends (5'-RACE), and reverse transcription-PCR analyses of five adenomas with a normal karyotype revealed fusion transcripts in three tumors. Nucleotide sequence analysis of these showed that they contained fusions between PLAG1 and CTNNB1 (one case) or PLAG1 and a novel fusion partner gene, i.e., the gene encoding the transcription elongation factor SII (two cases). The fusions occurred in the 5' noncoding region of PLAG1, leading to exchange of regulatory control elements and, as a consequence, activation of PLAG1 gene expression. Because all of the cases had grossly normal karyotypes, the rearrangements must result from cryptic rearrangements. The results suggest that in addition to chromosomal translocations and cryptic rearrangements, PLAG1 may also be activated by mutations or indirect mechanisms. Our findings establish a conserved mechanism of PLAG1 activation in salivary gland tumors with and without 8q12 aberrations, which indicates that such activation is a frequent event in these tumors.

Kim HS, Yang C, Kim KS
The cell-specific silencer region of the human dopamine beta-hydroxylase gene contains several negative regulatory elements.
J Neurochem. 1998; 71(1):41-50 [PubMed] Related Publications
Dopamine beta-hydroxylase (DBH) catalyzes the conversion of dopamine to noradrenaline and is selectively expressed in noradrenergic and adrenergic neurons in the nervous system. Transient transfection assays have indicated that cell-specific transcription of the human DBH gene may require a cell-specific silencer region residing at -486 to -263 bp upstream of the transcription start site. This region includes a putative DBH negative regulatory element (DNRE) with sequence homology to the restrictive element-1 (RE1)/neuron-restrictive silencer element identified in many other neural-specific genes. However, DNRE exerted negative regulation in both neuronal and nonneuronal cells alike, and site-directed mutation of this element did not significantly diminish the repressive activity of the DBH silencer region. Furthermore, expression of RE1-silencing transcription factor/neuron-restrictive silencer factor repressed neither DBH nor tyrosine hydroxylase promoter activity. We now report identification of three protein binding sites in the silencer region of the human DBH gene: SI at -271 to -250 bp, SII at -316 to -295 bp, and SIII at -348 to -324 bp. In vitro binding studies showed that SI and SIII, but not SII, interact with nuclear proteins from DBH-negative cells in a cell-specific manner. Furthermore, SI and SIII preferentially repressed the heterologous thymidine kinase and homologous DBH proximal promoter activities in nonneuronal cells. Taken together, the cell-specific silencer function of the upstream DBH region appears to involve several cis-regulatory elements, including two cell-specific repressor elements, SI and SIII, and a general negative regulatory element, DNRE. Based on these data, we propose that a highly restricted pattern of DBH gene expression in (nor)adrenergic cells of the nervous system may be controlled by multiple negative regulatory elements/silencers.

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