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Transcriptional regulation of genes expressed in the parathyroid gland
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
1999 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A dynamic interplay between promoter sequences and transcription factors ensures that genes are expressed at appropriate levels in each cell throughout the body. In the present investigation, the promoters of two different genes encoding proteins involved in parathyroid cell function and calcium homeostasis were studied.

Megalin/LRP-2 is an endocytic receptor which plays a crucial role in renal uptake and activation of vitamin D3, and may be involved in calcium sensing in the parathyroid cell. Characterization of the promoter for the human LRP-2 gene revealed that efficient transcription is dependent on two GC box elements, binding sites for transcription factors of the Sp family. In addition, a weak, atypical TATA box and a previously unknown sequence element located immediately downstream of the transcription start site were necessary for promoter activity. DNase I footprinting studies suggested a novel mechanism for downstream promoter element function involving qualitative effects on the transcription factor IID (TFIID)-TATA box interaction. Further analysis identified theLRP-2 gene 5'-flanking region and first exon as a CpG island, the methylation of which correlated inversely with gene expression in cultured cell lines. No evidence was found for aberrant LRP-2 gene methylation in parathyroid adenomas, in which the LRP-2 protein generally is downregulated.

Expression of the parathyroid hormone (PTH) gene is restricted to parathyroid glands, and is known to be negatively regulated by vitamin D3. Detailed functional analysis presented here revealed that PTH promoter activity requires a GC box, which was bound by transcription factors Sp1 and Sp3. In addition, inhibition of histonedeacetylases (HDACs) strongly stimulated PTH promoter activity, in a GC box dependent fashion. It was shown that Sp3, but not Sp1, mediated this activity via interaction with a complex containing the corepressor mSin3 and HDAC1. These results suggest a mechanism for transcriptional repression by Sp3, and furthermore that theactivity of the PTH gene, and possibly also of other genes containing GC boxes in their promoters, such as LRP-2, may be regulated at the chromatin level.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 1999. , 70 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 865
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URN: urn:nbn:se:uu:diva-999ISBN: 91-554-4543-8OAI: oai:DiVA.org:uu-999DiVA: diva2:173339
Public defence
1999-10-15, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala Universitet, Uppsala, 09:15
Available from: 1999-09-24 Created: 1999-09-24Bibliographically approved

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