Purification and characterization of thyroid transcription factor 2

Civitareale, Donato; Saiardi, Adolfo; Falasca, P.

doi:10.1042/bj3040981

Cited by 53 publications

(29 citation statements)

References 28 publications

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“…Recently, it has been shown that expansions of polyA tracts could result in protein misfolding and aggregation, which is toxic for the cells (Caburet et al 2004). Moreover, alanine tracts of some transcription factors have been suggested to be involved in the ability to transactivate or repress the expression of target genes (Civitareale et al 1994;Chadwick et al 1997;Lavoie et al 2003).…”

Section: Introductionmentioning

confidence: 99%

Polymorphic length of FOXE1 alanine stretch: evidence for genetic susceptibility to thyroid dysgenesis

et al. 2007

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Familial cases of congenital hypothyroidism from thyroid dysgenesis (TD) (OMIM 218700) occur with a frequency 15-fold higher than by chance, FOXE1 is one of the candidate genes for this genetic predisposition and contains an alanine tract. Our purpose is to assess the influence of length of the alanine tract of FOXE1 on genetic susceptibility to TD. A case-control association study (based on 115 patients affected by TD and 129 controls genotyped by direct sequencing) and transmission disequilibrium testing (TDT) analyses were performed. The transcriptional activities of FOXE1 constructs containing 14 or 16 alanines were also studied. In the case-control association study, the 16/16 and 16/14 genotypes were inversely associated with TD (OR = 0.39, 95%CI = 0.22-0.68, P = 0.0005), strongly suggesting that the presence of 16 alanines in the tract protect against the occurrence of TD. This association was stronger in the subgroup of patients with ectopic thyroid (OR = 0.28, 95%CI = 0.13-0.58, P = 0.00015). The protection was confirmed by the TDT analysis performed in 39 trios (chi(2) = 4.3, P = 0.0374). Alternatively, the presence of the 14/14 genotype is associated with an increase risk of TD (OR = 2.59, 95%CI = 1.56-4.62, P = 0.0005). The expression studies showed that the transcriptional activities of FOXE1 with 16 alanines were significantly higher (1.55-fold) than FOXE1 containing 14 alanines (P < 0.003), while the nuclear localisation of the proteins was not affected. We conclude that FOXE1 through its alanine containing stretch modulates significantly the risk of TD occurrence, enhancing a mechanism linking an alanine containing transcription factor to disease.

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Section: Introductionmentioning

confidence: 99%

Polymorphic length of FOXE1 alanine stretch: evidence for genetic susceptibility to thyroid dysgenesis

et al. 2007

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“…orkhead box E1/thyroid transcription factor 2 (FOXE1, also known as TTF2 or TITF2) is a forkhead/winged helixdomain containing protein (1). FOXE1 was initially characterized as a thyroid-specific transcription factor that binds to both the thyroglobulin (TG) and thyroid peroxidase (TPO) gene promoters, two thyroid differentiation markers (2,3).…”

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confidence: 99%

A NovelFOXE1Mutation (R73S) in Bamforth–Lazarus Syndrome Causing Increased Thyroidal Gene Expression

Carré

Hamza

Kariyawasam

et al. 2014

Thyroid

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Background: Homozygous loss-of-function mutations in the FOXE1 gene have been reported in several patients with partial or complete Bamforth-Lazarus syndrome: congenital hypothyroidism (CH) with thyroid dysgenesis (usually athyreosis), cleft palate, spiky hair, with or without choanal atresia, and bifid epiglottis. Here, our objective was to evaluate potential functional consequences of a FOXE1 mutation in a patient with a similar clinical phenotype. Methods: FOXE1 was sequenced in eight patients with thyroid dysgenesis and cleft palate. Transient transfection was performed in HEK293 cells using the thyroglobulin (TG) and thyroid peroxidase (TPO) promoters in luciferase reporter plasmids to assess the functional impact of the FOXE1 mutations. Primary human thyrocytes transfected with wild type and mutant FOXE1 served to assess the impact of the mutation on endogenous TG and TPO expression. Results: We identified and characterized the function of a new homozygous FOXE1 missense mutation (p.R73S) in a boy with a typical phenotype (athyreosis, cleft palate, and partial choanal atresia). This new mutation located within the forkhead domain was inherited from the heterozygous healthy consanguineous parents. In vitro functional studies in HEK293 cells showed that this mutant gene enhanced the activity of the TG and TPO gene promoters (1.5-fold and 1.7-fold respectively vs. wild type FOXE1; p < 0.05), unlike the five mutations previously reported in Bamforth-Lazarus syndrome. The gain-of-function effect of the FOXE1-p.R73S mutant gene was confirmed by an increase in endogenous TG production in primary human thyrocytes. Conclusion: We identified a new homozygous FOXE1 mutation responsible for enhanced expression of the TG and TPO genes in a boy whose phenotype is similar to that reported previously in patients with loss-of-function FOXE1 mutations. This finding further delineates the role for FOXE1 in both thyroid and palate development, and shows that enhanced gene activity should be considered among the mechanisms underlying Bamforth-Lazarus syndrome.

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“…Degradation of IKB has been suggested to involve ROS, as antioxidants block NF-KB activation, and potent NF-KB activators such as tumor necrosis factor-a, interlukin-1, phorbol 12-myristate 13-acetate (PMA), lipopolysaccharide and okadaic acid all elevate ROS levels (Schreck et al, 1991;Schreck et al, 1992). Redox regulation also has been suggested for the c-myb protooncogene (Guehmann et al, 1992), Ets transcription factor (Wasylyk and Wasylyk, 1993), SP-1 transcription factor (Knoepfel et al, 1994), glucocorticoid receptor (Esposito et al, 1995), early growth response-1 transcription factor (Huang and Adamson, 1993), thyroid transcription factors (Civitareale et al, 1994;Arnone et al, 1995), upstream stimulatory transcription factor (Pognonec et al, 1992), aryl hydrocarbon receptor (Ireland et al, 1995), and estrogen receptor (Hayashi et al, 1997). Oxidants also may stimulate signal transduction by altering ca2+.flux and protein phosphorylation (see ).…”

Section: Polychlorinated Biphenylsmentioning

confidence: 99%

Involvement of Cytochrome P450 1A in the toxicity of aryl hydrocarbon receptor agonists : alteration arachidonic acid metabolism and production of reactive oxygen species

Schlezinger¹

1998

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Purification and characterization of thyroid transcription factor 2

Cited by 53 publications

References 28 publications

Polymorphic length of FOXE1 alanine stretch: evidence for genetic susceptibility to thyroid dysgenesis

Polymorphic length of FOXE1 alanine stretch: evidence for genetic susceptibility to thyroid dysgenesis

A NovelFOXE1Mutation (R73S) in Bamforth–Lazarus Syndrome Causing Increased Thyroidal Gene Expression

Involvement of Cytochrome P450 1A in the toxicity of aryl hydrocarbon receptor agonists : alteration arachidonic acid metabolism and production of reactive oxygen species

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