Alternative splicing of iodothyronine deiodinases in pituitary adenomas. Regulation by oncoprotein SF2/ASF

Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, ul. Marymoncka 99/103, 01-813 Warsaw, Poland. Electronic address: .
Biochimica et Biophysica Acta (Impact Factor: 4.66). 02/2013; 1832(6). DOI: 10.1016/j.bbadis.2013.02.013
Source: PubMed


Pituitary tumors belong to the group of most common neoplasms of the sellar region. Iodothyronine deiodinase types 1 (DIO1) and 2 (DIO2) are enzymes contributing to the levels of locally synthesized T3, a hormone regulating key physiological processes in the pituitary, including its development, cellular proliferation, and hormone secretion. Previous studies revealed that the expression of deiodinases in pituitary tumors is variable and, moreover, there is no correlation between mRNA and protein products of the particular gene, suggesting the potential role of posttranscriptional regulatory mechanisms. In this work we hypothesized that one of such mechanisms could be the alternative splicing. Therefore, we analyzed expression and sequences of DIO1 and DIO2 splicing variants in 30 pituitary adenomas and 9 non-tumorous pituitary samples. DIO2 mRNA was expressed as only two mRNA isoforms. In contrast, nine splice variants of DIO1 were identified. Among them, five were devoid of exon 3. In silico sequence analysis of DIO1 revealed multiple putative binding sites for splicing factor SF2/ASF, of which the top-ranked sites were located in exon 3. Silencing of SF2/ASF in pituitary tumor GH3 cells resulted in change of ratio between DIO1 isoforms with or without exon 3, favoring the expression of variants without exon 3. The expression of SF2/ASF mRNA in pituitary tumors was increased when compared with non-neoplastic control samples. In conclusion, we provide a new mechanism of posttranscriptional regulation of DIO1 and show deregulation of DIO1 expression in pituitary adenoma, possibly resulting from disturbed expression of SF2/ASF.

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    ABSTRACT: The present study is aimed to present the potential role of thyroid hormones (TH) in the pathogenesis of glioblastoma multiforme (GBM). In first part of this presentation the effect of general homeostasis of TH on GBM formation and course was shown. Then the evidence concerning present state of the knowledge about active transport of TH to the brain, the role of iodothyronine deiodinase type 2 and 3 in the setting concentration of T3 in the brain and GBM cells, and finally knowledge about the role of genomic (TH nuclear receptors THRA and THRB) and non-genomic modes (membrane integrin receptor αvβ3) of action of TH and its importance for GBM was outlined. The last part of this presentation was devoted to generally approved signalling pathways leading to the formation and the clinical course of GBM, showing at the same time evidence that each of the pathways is affected by particular TH actions. In conclusion it is suggested that TH is one of the pathogenetic factors for GBM and as such can have practical implications for the formation and course and treatment of this tumour. (Endokrynol Pol 2015; 66 (5): 444-459).
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