The Experts below are selected from a list of 2433 Experts worldwide ranked by ideXlab platform
Pilar Santisteban - One of the best experts on this subject based on the ideXlab platform.
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FOXE1 regulates migration and invasion in thyroid cancer cells and targets zeb1
Endocrine-related Cancer, 2020Co-Authors: Jesus Morillobernal, Lara P Fernandez, Pilar SantistebanAbstract:FOXE1 is a thyroid-specific transcription factor essential for thyroid gland development and maintenance of the differentiated state. Interestingly, a strong association has been recently described between FOXE1 expression and susceptibility to thyroid cancer, but little is known about the mechanisms underlying FOXE1-induced thyroid tumorigenesis. Here, we used a panel of human thyroid cancer-derived cell lines covering the spectrum of thyroid cancer phenotypes to examine FOXE1 expression and to test for correlations between FOXE1 expression, the allele frequency of two SNPs and a length polymorphism in or near the FOXE1 locus associated with cancer susceptibility, and the migration ability of thyroid cancer cell lines. Results showed that FOXE1 expression correlated with differentiation status according to histological sub-type, but not with SNP genotype or cell migration ability. However, loss-and-gain-of-function experiments revealed that FOXE1 modulates cell migration, suggesting a role in epithelial-to-mesenchymal transition (EMT). Our previous genome-wide expression analysis identified Zeb1, a major EMT inducer, as a putative FOXE1 target gene. Indeed, gene silencing of FOXE1 decreased ZEB1 expression, whereas its overexpression increased ZEB1 transcriptional activity. FOXE1 was found to directly interact with the ZEB1 promoter. Lastly, ZEB1 silencing decreased the ability of thyroid tumoral cells to migrate and invade, pointing to its importance in thyroid tumor mestastases. In conclusion, we have identified ZEB1 as a bona fide target of FOXE1 in thyroid cancer cells, which provides new insights into the role of FOXE1 in regulating cell migration and invasion in thyroid cancer.
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new insights into FOXE1 functions identification of direct FOXE1 targets in thyroid cells
PLOS ONE, 2013Co-Authors: Lara P Fernandez, Aristides Lopezmarquez, Angel M Martinez, Gonzalo Gomezlopez, Pilar SantistebanAbstract:Background FOXE1 is a thyroid-specific forkhead transcription factor essential for thyroid gland development, as well as for the maintenance of the thyroid differentiated state in adults. FOXE1 recognizes and binds to a short DNA sequence present in thyroglobulin (Tg) and thyroperoxidase (Tpo) promoters, but FOXE1 binding to regulatory regions other than Tg and Tpo promoters remains almost unexplored. Improving knowledge of the regulatory functions of FOXE1 is necessary to clarify its role in endocrine syndromes and cancer susceptibility.
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the forkhead factor FOXE1 binds to the thyroperoxidase promoter during thyroid cell differentiation and modifies compacted chromatin structure
Molecular and Cellular Biology, 2007Co-Authors: Isabel Cuesta, Kenneth S Zaret, Pilar SantistebanAbstract:The Forkhead box (Fox) transcription factors play diverse roles in differentiation, development, hormone responsiveness, and aging. A pioneer activity of the Forkhead factors in developmental processes has been reported, but how this may apply to other contexts of Forkhead factor regulation remains unexplored. In this study, we address the pioneer activity of the thyroid-specific factor FOXE1 during thyroid differentiation. In response to hormone induction, FOXE1 binds to the compacted chromatin of the inactive thyroperoxidase (TPO) promoter, which coincides with the appearance of strong DNase I hypersensitivity at the FOXE1 binding site. In vitro, FOXE1 can bind to its site even when this is protected by a nucleosome, and it creates a local exposed domain specifically on H1-compacted TPO promoter-containing nucleosome arrays. Furthermore, nuclear factor 1 binds to the TPO promoter simultaneously with FOXE1, and this binding has an additive effect on FOXE1-mediated chromatin structure alteration. On the basis of our findings, we propose that FOXE1 is a pioneer factor whose primary mechanistic role in mediating the hormonal regulation of the TPO gene is to enable other regulatory factors to access the chromatin. The presented model extends the reported pioneer activity of the Forkhead factors to processes involved in hormone-induced differentiation.
Mario Venza - One of the best experts on this subject based on the ideXlab platform.
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msx1 and tgf β3 are novel target genes functionally regulated by FOXE1
Human Molecular Genetics, 2011Co-Authors: Isabella Venza, Maria Visalli, Diana Teti, Luca Parrillo, Mario De Felice, Mario VenzaAbstract:FOXE1 mutations cause the Bamforth–Lazarus syndrome characterized by thyroid and craniofacial defects. Although a pioneer activity of FOXE1 in thyroid development has been reported, FOXE1 regulation in other contexts remains unexplored. We pointed to: (i) a role of FOXE1 in controlling the expression of MSX1 and TGF-β3 relevant in craniofacial development and (ii) a causative part of FOXE1 mutations or mice FOXE1 –/– genotype in the pathogenesis of cleft palate in the Bamforth–Lazarus syndrome. The MSX1 and TGF-β3 up-regulation in response to FOXE1 at both transcriptional and translational levels and the recruitment of FOXE1 to specific binding motifs, together with the transactivation of the promoters of these genes, indicate that MSX1 and TGF-β3 are direct FOXE1 targets. Moreover, we showed that all the known forkhead-domain mutations, but not the polyalanine-stretch polymorphisms, affect the FOXE1 ability to bind to and transactivate MSX1 and TGF-β3 promoters. In 14-day FOXE1 –/– mice embryos, Tgf-β3 and Msx1 mRNAs were almost absent in palatal shelves compared with FOXE1 +/ – embryos. Our findings give new insights into the genetic mechanisms underlying the Bamforth–Lazarus syndrome-associated facial defects.
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FOXE1 is a target for aberrant methylation in cutaneous squamous cell carcinoma
British Journal of Dermatology, 2010Co-Authors: Isabella Venza, Maria Visalli, Diana Teti, B Tripodo, G De Grazia, S Loddo, Mario VenzaAbstract:Summary Background Several cancer-related genes are silenced by promoter hypermethylationin skin cancers. However, to date the somatic epigenetic events that occur in cu-taneous squamous cell carcinoma (SCC) tumorigenesis have not been welldefined.Objectives To examine epigenetic abnormalities of FOXE1, a gene located on chro-mosome 9q22, a region frequently lost in SCC.Methods We investigated the methylation status of FOXE1 in 60 cases of cutaneousSCC by methylation-specific polymerase chain reaction, and comparatively exam-ined mRNA and protein expression by real-time polymerase chain reaction andWestern blot, respectively.Results We found a higher frequency of FOXE1 promoter hypermethylation in SCCs(55%), as compared with the adjacent uninvolved skin (12%) and blood controlsamples (9AE5%). FOXE1 methylation was frequently seen in association with acomplete absence of or downregulated gene expression. Treatment with thedemethylating agent 5-Aza-2¢-deoxycytidine resulted in profound reactivation ofFOXE1 expression.Conclusions These results indicate that FOXE1 is a crucial player in development ofcutaneous SCC.
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investigation into FOXE1 genetic variations in cutaneous squamous cell carcinoma
British Journal of Dermatology, 2010Co-Authors: Isabella Venza, Maria Visalli, Diana Teti, B Tripodo, M Lentini, Mario VenzaAbstract:Summary Background FOXE1 is a candidate tumour suppressor gene at human chromosomelocus 9q22. This is a region frequently lost in squamous cell cancer.Objectives To assess the influence of FOXE1 variations on genetic susceptibility tocutaneous squamous cell carcinoma (SCC).Methods We performed mutational analysis of FOXE1 in 320 DNA samples isolatedfrom 60 SCC specimens, 60 adjacent histologically normal skin samples and 200blood samples.Results No somatic mutations were evident. Instead the polyalanine tract showedmarked variation in its length between samples from patients with SCC and nor-mal controls.Conclusions These results imply that another tumour suppressor gene at this locusmay be more important than FOXE1 in skin carcinogenesis and suggest that varia-tion in the FOXE1 polyalanine tract length predisposes to cutaneous SCC. Forkhead box E1 (FOXE1), formerly known as thyroid tran-scription factor 2 (TTF2), belongs to a large family of tran-scription factors characterized by their evolutionarilyconserved 110 amino acid DNA-binding domain, known asthe forkhead domain. Many members of this family are keyregulators of embryogenesis and play important roles in cellgrowth and differentiation, and a number of them areinvolved directly in the process of tumorigenesis.
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altered binding of myf 5 to FOXE1 promoter in non syndromic and charge associated cleft palate
Journal of Oral Pathology & Medicine, 2008Co-Authors: Mario Venza, Maria Visalli, Isabella Venza, Claudia Torino, Barbara Tripodo, Rocco Melita, Diana TetiAbstract:BACKGROUND: Three different homozygous loss-offunction mutations of the Forkhead box E1 (FOXE1) gene have been associated with syndromic cleft palate. Here, we screened the entire promoter region to identify the variations in significant consensus motifs affecting FOXE1 transcription. METHOD: Genomic DNAs of 35 cleft palate patients, 10 of whom with CHARGE association, 80 unrelated healthy people and 80 unaffected first-degree relatives were analysed by automatic sequencing. The Transcription Element Search System program was employed to identify transcription factor binding sites. The proteinDNA complexes were observed using DNA band-shift assays and oligonucleotide competition analyses. Realtime PCR was used to estimate FOXE1 expression at mRNA level. RESULTS: In 11 non-syndromic cleft palate patients, a novel non-coding polymorphism (C fi G) in the 5¢-untranslated region of FOXE1 was found. The variation fell into a putative consensus sequence for the transcription factor MYF-5 and completely impaired the ability of MYF-5 to bind to its motif, as shown by EMSA experiments. As a consequence, a significantly reduced FOXE1 mRNA expression was observed. CONCLUSIONS: In 45% % of non-syndromic cleft palate patients, a novel homozygous polymorphism that prevented the binding of MYF-5 to FOXE1 promoter and affected the FOXE1 expression was found. As recent data show the role of MYF-5 in the muscle-dependent craniofacial skeletal development and in the fusion of primary palate and secondary palate, the results reported here strongly suggest a more significant involvement of this factor in the cleft palate onset. J Oral Pathol Med (2009) 38: 18–23
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FOXE1 gene mutation screening by multiplex pcr dhplc in charge syndrome and syndromic and non syndromic cleft palate
Journal of Chromatography B, 2006Co-Authors: Mario Venza, Maria Visalli, Isabella Venza, Claudia Torino, Rita Saladino, Diana TetiAbstract:Denaturing high-performance liquid chromatography (DHPLC) has established itself as one of the most powerful tools for DNA variation screening. FOXE1, a highly GC-rich gene involved in syndromic cleft palate, is under investigation in thyroid dysgenesis, nonsyndromic cleft palate and squamous cell carcinoma. A technique for fast and simultaneous detection of sequence variants in the entire coding region of the FOXEl gene based on multiplex PCR/DHPLC is presented here. Given its characteristics of high sensitivity and rapidity, the testing strategy developed by us appears to be a reliable approach for FOXE1 analysis in the screening of a large population at risk.
Stan B Sidhu - One of the best experts on this subject based on the ideXlab platform.
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association of FOXE1 polyalanine repeat region with papillary thyroid cancer
The Journal of Clinical Endocrinology and Metabolism, 2012Co-Authors: Martyn Bullock, Emma L Duncan, Christine J Oneill, Lyndal J Tacon, Mark Sywak, Stan B SidhuAbstract:Context: Polyalanine tract variations in transcription factors have been identified for a wide spectrum of developmental disorders. The thyroid transcription factor forkhead factor E1 (FOXE1) contains a polymorphic polyalanine tract with 12–22 alanines. Single-nucleotide polymorphisms (SNP) close to this locus are associated with papillary thyroid cancer (PTC), and a strong linkage disequilibrium block extends across this region. Objective: The objective of the study was to assess whether the FOXE1 polyalanine repeat region was associated with PTC and to assess the effect of polyalanine repeat region variants on protein expression, DNA binding, and transcriptional function on FOXE1-responsive promoters. Design: This was a case-control study. Setting: The study was conducted at a tertiary referral hospital. Patients and Methods: The FOXE1 polyalanine repeat region and tag SNP were genotyped in 70 PTC, with a replication in a further 92 PTC, and compared with genotypes in 5767 healthy controls (including 56...
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association of FOXE1 polyalanine repeat region with papillary thyroid cancer
Faculty of Health; Institute of Health and Biomedical Innovation, 2012Co-Authors: Martyn Bullock, Emma L Duncan, Christine J Oneill, Lyndal J Tacon, Mark Sywak, Stan B SidhuAbstract:CONTEXT: Polyalanine tract variations in transcription factors have been identified for a wide spectrum of developmental disorders. The thyroid transcription factor forkhead factor E1 (FOXE1) contains a polymorphic polyalanine tract with 12-22 alanines. Single-nucleotide polymorphisms (SNP) close to this locus are associated with papillary thyroid cancer (PTC), and a strong linkage disequilibrium block extends across this region. OBJECTIVE: The objective of the study was to assess whether the FOXE1 polyalanine repeat region was associated with PTC and to assess the effect of polyalanine repeat region variants on protein expression, DNA binding, and transcriptional function on FOXE1-responsive promoters. DESIGN: This was a case-control study. SETTING: The study was conducted at a tertiary referral hospital. PATIENTS AND METHODS: The FOXE1 polyalanine repeat region and tag SNP were genotyped in 70 PTC, with a replication in a further 92 PTC, and compared with genotypes in 5767 healthy controls (including 5667 samples from the Wellcome Trust Case Control Consortium). In vitro studies were performed to examine the protein expression, DNA binding, and transcriptional function for FOXE1 variants of different polyalanine tract lengths. RESULTS: All the genotyped SNP were in tight linkage disequilibrium, including the FOXE1 polyalanine repeat region. We confirmed the strong association of rs1867277 with PTC (overall P = 1 × 10(-7), odds ratio 1.84, confidence interval 1.31-2.57). rs1867277 was in tight linkage disequilibrium with the FOXE1 polyalanine repeat region (r(2) = 0.95). FOXE1(16Ala) was associated with PTC with an odds ratio of 2.23 (confidence interval 1.42-3.50; P = 0.0005). Functional studies in vitro showed that FOXE1(16Ala) was transcriptionally impaired compared with FOXE1(14Ala), which was not due to differences in protein expression or DNA binding. CONCLUSIONS: We have confirmed the previous association of FOXE1 with PTC. Our data suggest that the coding polyalanine expansion in FOXE1 may be responsible for the observed association between FOXE1 and PTC.
Isabella Venza - One of the best experts on this subject based on the ideXlab platform.
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msx1 and tgf β3 are novel target genes functionally regulated by FOXE1
Human Molecular Genetics, 2011Co-Authors: Isabella Venza, Maria Visalli, Diana Teti, Luca Parrillo, Mario De Felice, Mario VenzaAbstract:FOXE1 mutations cause the Bamforth–Lazarus syndrome characterized by thyroid and craniofacial defects. Although a pioneer activity of FOXE1 in thyroid development has been reported, FOXE1 regulation in other contexts remains unexplored. We pointed to: (i) a role of FOXE1 in controlling the expression of MSX1 and TGF-β3 relevant in craniofacial development and (ii) a causative part of FOXE1 mutations or mice FOXE1 –/– genotype in the pathogenesis of cleft palate in the Bamforth–Lazarus syndrome. The MSX1 and TGF-β3 up-regulation in response to FOXE1 at both transcriptional and translational levels and the recruitment of FOXE1 to specific binding motifs, together with the transactivation of the promoters of these genes, indicate that MSX1 and TGF-β3 are direct FOXE1 targets. Moreover, we showed that all the known forkhead-domain mutations, but not the polyalanine-stretch polymorphisms, affect the FOXE1 ability to bind to and transactivate MSX1 and TGF-β3 promoters. In 14-day FOXE1 –/– mice embryos, Tgf-β3 and Msx1 mRNAs were almost absent in palatal shelves compared with FOXE1 +/ – embryos. Our findings give new insights into the genetic mechanisms underlying the Bamforth–Lazarus syndrome-associated facial defects.
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FOXE1 is a target for aberrant methylation in cutaneous squamous cell carcinoma
British Journal of Dermatology, 2010Co-Authors: Isabella Venza, Maria Visalli, Diana Teti, B Tripodo, G De Grazia, S Loddo, Mario VenzaAbstract:Summary Background Several cancer-related genes are silenced by promoter hypermethylationin skin cancers. However, to date the somatic epigenetic events that occur in cu-taneous squamous cell carcinoma (SCC) tumorigenesis have not been welldefined.Objectives To examine epigenetic abnormalities of FOXE1, a gene located on chro-mosome 9q22, a region frequently lost in SCC.Methods We investigated the methylation status of FOXE1 in 60 cases of cutaneousSCC by methylation-specific polymerase chain reaction, and comparatively exam-ined mRNA and protein expression by real-time polymerase chain reaction andWestern blot, respectively.Results We found a higher frequency of FOXE1 promoter hypermethylation in SCCs(55%), as compared with the adjacent uninvolved skin (12%) and blood controlsamples (9AE5%). FOXE1 methylation was frequently seen in association with acomplete absence of or downregulated gene expression. Treatment with thedemethylating agent 5-Aza-2¢-deoxycytidine resulted in profound reactivation ofFOXE1 expression.Conclusions These results indicate that FOXE1 is a crucial player in development ofcutaneous SCC.
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investigation into FOXE1 genetic variations in cutaneous squamous cell carcinoma
British Journal of Dermatology, 2010Co-Authors: Isabella Venza, Maria Visalli, Diana Teti, B Tripodo, M Lentini, Mario VenzaAbstract:Summary Background FOXE1 is a candidate tumour suppressor gene at human chromosomelocus 9q22. This is a region frequently lost in squamous cell cancer.Objectives To assess the influence of FOXE1 variations on genetic susceptibility tocutaneous squamous cell carcinoma (SCC).Methods We performed mutational analysis of FOXE1 in 320 DNA samples isolatedfrom 60 SCC specimens, 60 adjacent histologically normal skin samples and 200blood samples.Results No somatic mutations were evident. Instead the polyalanine tract showedmarked variation in its length between samples from patients with SCC and nor-mal controls.Conclusions These results imply that another tumour suppressor gene at this locusmay be more important than FOXE1 in skin carcinogenesis and suggest that varia-tion in the FOXE1 polyalanine tract length predisposes to cutaneous SCC. Forkhead box E1 (FOXE1), formerly known as thyroid tran-scription factor 2 (TTF2), belongs to a large family of tran-scription factors characterized by their evolutionarilyconserved 110 amino acid DNA-binding domain, known asthe forkhead domain. Many members of this family are keyregulators of embryogenesis and play important roles in cellgrowth and differentiation, and a number of them areinvolved directly in the process of tumorigenesis.
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altered binding of myf 5 to FOXE1 promoter in non syndromic and charge associated cleft palate
Journal of Oral Pathology & Medicine, 2008Co-Authors: Mario Venza, Maria Visalli, Isabella Venza, Claudia Torino, Barbara Tripodo, Rocco Melita, Diana TetiAbstract:BACKGROUND: Three different homozygous loss-offunction mutations of the Forkhead box E1 (FOXE1) gene have been associated with syndromic cleft palate. Here, we screened the entire promoter region to identify the variations in significant consensus motifs affecting FOXE1 transcription. METHOD: Genomic DNAs of 35 cleft palate patients, 10 of whom with CHARGE association, 80 unrelated healthy people and 80 unaffected first-degree relatives were analysed by automatic sequencing. The Transcription Element Search System program was employed to identify transcription factor binding sites. The proteinDNA complexes were observed using DNA band-shift assays and oligonucleotide competition analyses. Realtime PCR was used to estimate FOXE1 expression at mRNA level. RESULTS: In 11 non-syndromic cleft palate patients, a novel non-coding polymorphism (C fi G) in the 5¢-untranslated region of FOXE1 was found. The variation fell into a putative consensus sequence for the transcription factor MYF-5 and completely impaired the ability of MYF-5 to bind to its motif, as shown by EMSA experiments. As a consequence, a significantly reduced FOXE1 mRNA expression was observed. CONCLUSIONS: In 45% % of non-syndromic cleft palate patients, a novel homozygous polymorphism that prevented the binding of MYF-5 to FOXE1 promoter and affected the FOXE1 expression was found. As recent data show the role of MYF-5 in the muscle-dependent craniofacial skeletal development and in the fusion of primary palate and secondary palate, the results reported here strongly suggest a more significant involvement of this factor in the cleft palate onset. J Oral Pathol Med (2009) 38: 18–23
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FOXE1 gene mutation screening by multiplex pcr dhplc in charge syndrome and syndromic and non syndromic cleft palate
Journal of Chromatography B, 2006Co-Authors: Mario Venza, Maria Visalli, Isabella Venza, Claudia Torino, Rita Saladino, Diana TetiAbstract:Denaturing high-performance liquid chromatography (DHPLC) has established itself as one of the most powerful tools for DNA variation screening. FOXE1, a highly GC-rich gene involved in syndromic cleft palate, is under investigation in thyroid dysgenesis, nonsyndromic cleft palate and squamous cell carcinoma. A technique for fast and simultaneous detection of sequence variants in the entire coding region of the FOXEl gene based on multiplex PCR/DHPLC is presented here. Given its characteristics of high sensitivity and rapidity, the testing strategy developed by us appears to be a reliable approach for FOXE1 analysis in the screening of a large population at risk.
Martyn Bullock - One of the best experts on this subject based on the ideXlab platform.
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thyroid transcription factor FOXE1 interacts with ets factor elk1 to co regulate tert
Oncotarget, 2016Co-Authors: Martyn Bullock, Grace Lim, In Ho Choi, Shivansh Kochhar, Christopher Liddle, Lei Zhang, Roderick J CliftonblighAbstract:// Martyn Bullock 1 , Grace Lim 1 , Cheng Li 1, 2 , In Ho Choi 1, 2 , Shivansh Kochhar 1, 2 , Chris Liddle 2, 3 , Lei Zhang 4 , Roderick J. Clifton-Bligh 1, 2, 5 1 Cancer Genetics Laboratory, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia 2 University of Sydney, Sydney, Australia 3 Storr Liver Centre, Westmead Millennium Institute for Medical Research, Westmead Hospital, Sydney, Australia 4 Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Cardiff, UK 5 Department of Endocrinology, Royal North Shore Hospital, Sydney, Australia Correspondence to: Roderick J. Clifton-Bligh, email: jclifton@med.usyd.edu.au Keywords: thyroid cancer, BRAF-ERK pathway, FOXE1, ELK1, TERT Received: February 17, 2016 Accepted: November 06, 2016 Published: November 11, 2016 ABSTRACT Background: Although FOXE1 was initially recognized for its role in thyroid organogenesis, more recently a strong association has been identified between the FOXE1 locus and thyroid cancer. The role of FOXE1 in adult thyroid, and in particular regarding cancer risk, has not been well established. We hypothesised that discovering key FOXE1 transcriptional partners would in turn identify regulatory pathways relevant to its role in oncogenesis. Results: In a transcription factor-binding array, ELK1 was identified to bind FOXE1. We confirmed this physical association in heterologously transfected cells by IP and mammalian two-hybrid assays. In thyroid tissue, endogenous FOXE1 was shown to bind ELK1, and using ChIP assays these factors bound thyroid-relevant gene promoters TPO and TERT in close proximity to each other. Using a combination of electromobility shift assays, TERT promoter assays and siRNA-silencing, we found that FOXE1 positively regulated TERT expression in a manner dependent upon its association with ELK1. Treating heterologously transfected thyroid cells with MEK inhibitor U0126 inhibited FOXE1-ELK1 interaction, and reduced TERT and TPO promoter activity. Methodology: We investigated FOXE1 interactions within in vitro thyroid cell models and human thyroid tissue using a combination of immunoprecipitation (IP), chromatin IP (ChIP) and gene reporter assays. Conclusions: FOXE1 interacts with ELK1 on thyroid relevant gene promoters, establishing a new regulatory pathway for its role in adult thyroid function. Co-regulation of TERT suggests a mechanism by which allelic variants in/near FOXE1 are associated with thyroid cancer risk.
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somatic mutations of FOXE1 in papillary thyroid cancer
Thyroid, 2015Co-Authors: Michael Mond, Martyn Bullock, Roderick J Cliftonbligh, Yizhou Yao, Christopher Gilfillan, Peter J FullerAbstract:Background: Population-based studies have demonstrated an association of single nucleotide polymorphisms close to the thyroid transcription factor forkhead box E1 (FOXE1) gene with thyroid cancer. The dysregulation of forkhead proteins is increasingly recognized to play a role in the development and progression of cancer. The objective of the study was to seek to identify novel mutations in FOXE1 in papillary thyroid cancer (PTC) and to assess the effect of these mutations on protein expression and transcriptional function on FOXE1 responsive promoters. Methods: The study was conducted at two tertiary referral hospitals. The coding region of FOXE1 was sequenced in tissue-derived DNA or RNA from 120 patients with PTC and 110 patients with multinodular goiter (MNG). In vitro studies were performed to examine the protein expression and transcriptional function of FOXE1 mutants. A molecular model of the forkhead domain (FHD) of FOXE1 was generated using the SWISS-MODEL online server with the three-dimensional...
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association of FOXE1 polyalanine repeat region with papillary thyroid cancer
The Journal of Clinical Endocrinology and Metabolism, 2012Co-Authors: Martyn Bullock, Emma L Duncan, Christine J Oneill, Lyndal J Tacon, Mark Sywak, Stan B SidhuAbstract:Context: Polyalanine tract variations in transcription factors have been identified for a wide spectrum of developmental disorders. The thyroid transcription factor forkhead factor E1 (FOXE1) contains a polymorphic polyalanine tract with 12–22 alanines. Single-nucleotide polymorphisms (SNP) close to this locus are associated with papillary thyroid cancer (PTC), and a strong linkage disequilibrium block extends across this region. Objective: The objective of the study was to assess whether the FOXE1 polyalanine repeat region was associated with PTC and to assess the effect of polyalanine repeat region variants on protein expression, DNA binding, and transcriptional function on FOXE1-responsive promoters. Design: This was a case-control study. Setting: The study was conducted at a tertiary referral hospital. Patients and Methods: The FOXE1 polyalanine repeat region and tag SNP were genotyped in 70 PTC, with a replication in a further 92 PTC, and compared with genotypes in 5767 healthy controls (including 56...
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association of FOXE1 polyalanine repeat region with papillary thyroid cancer
Faculty of Health; Institute of Health and Biomedical Innovation, 2012Co-Authors: Martyn Bullock, Emma L Duncan, Christine J Oneill, Lyndal J Tacon, Mark Sywak, Stan B SidhuAbstract:CONTEXT: Polyalanine tract variations in transcription factors have been identified for a wide spectrum of developmental disorders. The thyroid transcription factor forkhead factor E1 (FOXE1) contains a polymorphic polyalanine tract with 12-22 alanines. Single-nucleotide polymorphisms (SNP) close to this locus are associated with papillary thyroid cancer (PTC), and a strong linkage disequilibrium block extends across this region. OBJECTIVE: The objective of the study was to assess whether the FOXE1 polyalanine repeat region was associated with PTC and to assess the effect of polyalanine repeat region variants on protein expression, DNA binding, and transcriptional function on FOXE1-responsive promoters. DESIGN: This was a case-control study. SETTING: The study was conducted at a tertiary referral hospital. PATIENTS AND METHODS: The FOXE1 polyalanine repeat region and tag SNP were genotyped in 70 PTC, with a replication in a further 92 PTC, and compared with genotypes in 5767 healthy controls (including 5667 samples from the Wellcome Trust Case Control Consortium). In vitro studies were performed to examine the protein expression, DNA binding, and transcriptional function for FOXE1 variants of different polyalanine tract lengths. RESULTS: All the genotyped SNP were in tight linkage disequilibrium, including the FOXE1 polyalanine repeat region. We confirmed the strong association of rs1867277 with PTC (overall P = 1 × 10(-7), odds ratio 1.84, confidence interval 1.31-2.57). rs1867277 was in tight linkage disequilibrium with the FOXE1 polyalanine repeat region (r(2) = 0.95). FOXE1(16Ala) was associated with PTC with an odds ratio of 2.23 (confidence interval 1.42-3.50; P = 0.0005). Functional studies in vitro showed that FOXE1(16Ala) was transcriptionally impaired compared with FOXE1(14Ala), which was not due to differences in protein expression or DNA binding. CONCLUSIONS: We have confirmed the previous association of FOXE1 with PTC. Our data suggest that the coding polyalanine expansion in FOXE1 may be responsible for the observed association between FOXE1 and PTC.
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Characterisation of a forkhead transcription factor: FOXE1.
2007Co-Authors: Martyn BullockAbstract:FOXE1, a forkhead transcription factor, plays an essential role in the development of the thyroid and hair follicle. Loss-of-function FOXE1 mutations cause aberrant morphogenesis of both tissues, apparently due to a defect in cell migration. In the mature thyroid, FOXE1 plays an essential role in the control of thyroid hormone synthesis, modulating both thyroglobulin and thyroid peroxidase gene expression. Several studies have shown there is considerable inter-individual variability in thyroid hormone levels, and this is due at least in part to genetic factors. One of the main features of the FOXE1 protein is a highly polymorphic polyalanine tract that can range in size from 11 to 19-Ala residues (wild-type being 14-Ala residues). The aims of this thesis were: 1) To determine the precise location of FOXE1 expression within the human hair follicle. 2) To identify genes involved in cell migration that could be potential FOXE1 target genes. 3) To investigate the possible role of FOXE1 polyalanine polymorphisms in thyroid dysfunction. 1) Immunohistochemical analysis confirmed previous observations that FOXE1 was expressed in human epidermis and hair follicle outer root sheath. However, technical difficulties prevented more detailed analyses (e.g. colocalisation with hair-specific proteins). 2) Bioinformatics yielded several potential FOXE1 target genes. Subsequent QPCR-based expression profiling and siRNA-based gene knockdown experiments suggested TIMP3 as a likely direct downstream target. Thus, FOXE1 may have a direct role in the modulation of ECM architecture by migratory cells. 3) The genotyping of a small cohort of subclinical hypothyroid subjects, showed there to be an increased incidence of the 16-Ala allele compared with the control group. Luciferase assays revealed the transcriptional activity of the 16-Ala allele to be significantly reduced compared with wild-type. This provides the first evidence that polymorphic variation can affect the transcriptional activity of FOXE1, and be a possible contributing factor in the sub-optimal thyroid function.
