Disease relevance of PAX8

• Mutations in the paired domain transcription factor PAX8 are a rare cause of congenital hypothyroidism due to thyroid dysgenesis [1].
• Our findings suggest that PAX8/PPAR gamma occurs frequently in follicular thyroid carcinomas, and the presence of this rearrangement is likely to prove highly suggestive of a malignant tumor [2].
• Detection of the PAX8-PPAR gamma fusion oncogene in both follicular thyroid carcinomas and adenomas [3].
• In an in vitro model of placental cancer, the JAR choriocarcinoma cell line, human chorionic gonadotropin (hCG) increased levels of PAX8 mRNA and protein, and gel retardation assays indicated that the up-regulation of PAX8 protein expression is associated with an increase in its DNA-binding activity [4].
• We investigated in a series of thyroid samples, including 14 normal, 13 hyperfunctioning tissues, 26 follicular adenomas, 21 follicular and 41 papillary carcinomas, both the frequency of the PAX8-PPARgamma1 rearrangement and the expression of the PAX8 and PPARgamma transcripts [5].

High impact information on PAX8

• PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis [6].
• All three point mutations are located in the paired domain of PAX8 and result in severe reduction of the DNA-binding activity of this transcription factor [6].
• The expression of PAX8 occurs in the induced mesenchyme of the developing kidney prior to the upregulation of WT1 levels in the same cells [7].
• We also demonstrate that the endogenous wt1 promoter can be upregulated by exogenously supplied PAX8, suggesting that a function of PAX8 during mesenchymal--epithelial cell transition in renal development is to induce wt1 gene expression [7].
• Transfection studies, as well as gel-shift assays, indicate that PAX8 transactivates wt1 through elements within a 38 bp conserved motif, present in human and murine promoters [7].

Biological context of PAX8

• Our results describe the first dominant negative missense mutation in a paired domain and provide evidence for a crucial role of the p300 coactivator in mediating the functional synergism between PAX8 and TTF-1 in thyroid-specific gene expression [1].
• In this study, a group of 87 thyroid tumors were analyzed to determine the involvement of the PAX8/PPAR gamma fusion gene in these tumors, and also to determine whether this rearrangement can be used as a diagnostic marker for the differentiation between follicular thyroid carcinoma and adenoma [2].
• A recent study of follicular thyroid carcinomas reported a novel chromosomal translocation, t(2;3)(q13;p25), that fused the thyroid-specific transcription factor PAX8 with a nuclear receptor, peroxisome proliferator-activated receptor gamma (PPAR gamma) [3].
• PAX8-peroxisome proliferator-activated receptor gamma (PPARgamma) disrupts normal PAX8 or PPARgamma transcriptional function and stimulates follicular thyroid cell growth [8].
• In this report, we describe the isolation and characterization of PAX8 cDNAs from a human adult kidney cDNA library [9].

Anatomical context of PAX8

• PAX8 was also expressed in the developing central nervous system and kidney, including the ureteric bud and the main collecting ducts [10].
• Interestingly, PAX8 was also expressed in the thyroglossal duct and the ultimobranchial bodies [10].
• Mutations in PAX8, TITF1, or FOXE1 may account for congenital hypothyroidism in patients with either isolated TD or TD with associated malformations involving kidney, lung, forebrain, and palate [10].
• In situ hybridization to sections of human embryonic and fetal kidney showed expression of PAX8 in condensed mesenchyme, comma-shaped and S-shaped bodies [9].
• RNA samples were electrophoretically separated in 1.2% agarose gels, transferred to nylon membranes, and hybridized to random primer-labeled PAX2, PAX8, and WT1 probes [11].

Associations of PAX8 with chemical compounds

• HEX, PAX-8 and TTF-1 gene expression in human thyroid tissues: a comparative analysis with other genes involved in iodide metabolism [12].
• Two independent cDNA clones reveal differential splicing of the PAX8 transcripts resulting in the removal of a 63 amino acid serine-rich region from the carboxy end of the predicted Pax8 protein [9].
• One patient was found to harbor a heterozygous transversion 119A-->C in exon 3 of PAX8 replacing a conserved glutamine by proline in the paired box domain (Q40P) [13].
• The mutation consists of the substitution of a tyrosine for cysteine 57 in the paired domain of PAX8 [14].
• Thyroid dysgenesis caused by PAX8 mutation: the hypermutability with CpG dinucleotides at codon 31 [15].

Physical interactions of PAX8

• Functional analyses of the PAX8 Q40P mutation showed impaired binding to a PAX8 response element and absent trans-activation of a thyroid peroxidase promoter luciferase reporter gene [13].
• In contrast, the previously reported core PAX 8-binding sites identified by computer analysis of the WT1 promoter failed to specifically bind in vitro translated PAX 8 protein or activate the minimal promoter [16].

Regulatory relationships of PAX8

• Thyroid transcription factor 1 and Pax8 synergistically activate the promoter of the human thyroglobulin gene [17].

Other interactions of PAX8

• Thyroid transcription factor 1 rescues PAX8/p300 synergism impaired by a natural PAX8 paired domain mutation with dominant negative activity [1].
• The mutant protein (PAX8-S48F) does not induce the thyroglobulin promoter in nonthyroid cells, but displays almost half of wild-type PAX8 activity in thyroid cells [1].
• Involvement of the PAX8/peroxisome proliferator-activated receptor gamma rearrangement in follicular thyroid tumors [2].
• They explain the malformations associated with TD in patients carrying PAX8, TITF1, and FOXE1 gene mutations [10].
• These findings indicate that, in JAR cells, hCG activates a cAMP-dependent pathway that can up-regulate WT1 expression through PAX8 [4].

Analytical, diagnostic and therapeutic context of PAX8

• The PAX8/PPAR gamma rearrangement was detected by RT-PCR, fluorescence in situ hybridization, and/or Western analysis in 10 of 34 (29%) follicular thyroid carcinomas and in one of 20 (5%) atypical follicular thyroid adenomas, but not in any of the 20 follicular thyroid adenomas or 13 anaplastic thyroid carcinomas studied [2].
• Concordant expression of protein was found in 91% of those tumors in which PAX8-PPAR gamma mRNA was detected by RT-PCR, whereas a further 20% of follicular tumors were positive for PPAR gamma immunohistochemistry alone [3].
• Our findings that PAX8-PPAR gamma 1 rearrangements are present in both follicular carcinomas and adenomas suggest that this oncogene is not a reliable marker to differentiate between FTC and FTA in fine-needle aspiration biopsies of follicular neoplasms of the thyroid [18].
• The entire PAX8 coding region with exon-intron boundaries was amplified from genomic DNA, and a mutational screening was performed by denaturing HPLC followed by direct sequencing when denaturing HPLC elution abnormalities appeared [19].
• Fifty-four subjects with congenital hypothyroidism detected during neonatal screening and associated with an ultrasound or scintiscan picture of thyroid dysgenesis were investigated for PAX8 mutations [19].

References