uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Stabilizing mutations of CTNNB1/β-catenin in parathyroid adenomas of Swedish patients.
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
Article in journal (Refereed) Submitted
URN: urn:nbn:se:uu:diva-96471OAI: oai:DiVA.org:uu-96471DiVA: diva2:171052
Available from: 2007-11-16 Created: 2007-11-16Bibliographically approved
In thesis
1. Wnt/β-Catenin Signalling in Parathyroid Tumours
Open this publication in new window or tab >>Wnt/β-Catenin Signalling in Parathyroid Tumours
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Primary hyperparathyroidism (pHPT) due to parathyroid tumours with hypersecretion of parathyroid hormone and hypercalcaemia is a common disease with incompletely understood etiology affecting more than 1 % of the population, primarily postmenopausal women. In secondary hyperparathyroidism (sHPT), parathyroid tumours develop in response to calcium and vitamin D deficiency generally in patients with uraemia. HPT is usually treated by surgical removal of enlarged parathyroid glands.

The aim of this thesis was to examine the Wnt/β-catenin signalling pathway in parathyroid tumours.

Aberrantly accumulated β-catenin was found in all analysed pHPT and sHPT tumours, with a stabilising homozygous mutation (Ser37Ala) in 7.3% of the pHPT tumours. Truncation of the APC protein was not found. MYC, a β-catenin target gene was overexpressed in a substantial fraction of pHPT and sHPT parathyroid tumours.

A parathyroid tumour cell line (sHPT-1) was established from a hyperplastic gland removed at operation of a patient with sHPT. The cells produced parathyroid hormone and grew with a doubling time of approximately 72 hours. Stabilised nonphosphorylated transcriptionally active β-catenin was expressed. Efficient transfection of siRNA against β-catenin decreased expression of cyclin D1 and MYC, and inhibited cell growth with ensuring cell death.

The Wnt coreceptor LRP5 was found expressed with an internal deletion of 142 amino acids (LRP5Δ) in 86% and 100% of pHPT and sHPT tumours, respectively. Stabilising mutation of β-catenin and expression of LRP5Δ was mutually exclusive. Expression of LRP5Δ was required to maintain the nonphosphorylated transcriptionally active ß-catenin level, MYC expression, parathyroid cell growth in vitro, and tumour growth in transplanted SCID mice. Wnt3 ligand and LRP5Δ strongly activated transcription, and LRP5Δ was insensitive to inhibition by DKK1.

Aberrant accumulation of β-catenin by stabilising mutation or expression of LRP5Δ appears as a common pathogenic pathway for hyperparathyroid disease. LRP5Δ in particular presents a potential target for therapeutic intervention.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 63 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 293
Surgery, Hyperparathyroidism, β-catenin, Mutation, Human parathyroid cell line, LRP5, Alternative splicing, Kirurgi
urn:nbn:se:uu:diva-8317 (URN)978-91-554-7029-6 (ISBN)
Public defence
2007-12-08, Enghoffsalen, Entre 50, Akademiska sjukhuset, Uppsala, 09:15
Available from: 2007-11-16 Created: 2007-11-16Bibliographically approved

Open Access in DiVA

No full text

By organisation
Department of Surgical Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Total: 189 hits
ReferencesLink to record
Permanent link

Direct link