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Notch signaling factors in the transforming Men1 mouse pancreas
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
(English)Manuscript (preprint) (Other academic)
National Category
Other Basic Medicine
Identifiers
URN: urn:nbn:se:uu:diva-177595OAI: oai:DiVA.org:uu-177595DiVA: diva2:541213
Available from: 2012-07-16 Created: 2012-07-16 Last updated: 2018-01-12
In thesis
1. The MEN 1 Pancreas: Tumor Development and Haploinsufficiency
Open this publication in new window or tab >>The MEN 1 Pancreas: Tumor Development and Haploinsufficiency
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Multiple Endocrine Neoplasia Type I Syndrome (MEN 1) is a monogenic autosomal dominantly inherited cancer syndrome caused by a heterozygous loss of the MEN1 gene, predisposing for endocrine cell proliferation and tumor formation. MEN 1 carriers classically develop tumors in endocrine organs; the parathyroids, the endocrine pancreas, and the pituitary. Other organs, endocrine and non-endocrine, may also be affected. The most common cause of death in MEN 1 is pancreatic endocrine tumor (PNET), which exhibit inactivation of both MEN1 alleles. The increased proliferation prior to loss of the wild-type allele indicates haploinsufficiency, and little is known concerning the mechanisms behind MEN 1 PNET development. The MEN1 protein, menin, lacking homology with other known proteins, is involved in several aspects of transcriptional regulation and chromatin organization.

We report differential expression and subcellular localization of transcription factors important in pancreatic development, in human and mouse MEN 1 pancreas, compared to non-MEN 1 pancreas. A predominantly cytoplasmic localization of Neurogenin3 and NeuroD1 was observed in tumors as well as in MEN 1 non-tumorous pancreas.

Notch signaling factor expression and localization were examined in the pancreas of a heterozygous Men1 mouse model, and compared with that of wild-type littermates. Nuclear Hes1 was lost in tumors, concomitant to weaker Notch1 NICD expression, and further, analyzed using qPCR, it was shown that Notch1 was less expressed in heterozygous islets compared to wild-type islets.

Performing a global gene expression array, we identified differential gene expression in five-week-old heterozygous Men1 mouse islets, compared to islets from wild-type littermates. The array results for a subset of the differentially regulated genes were corroborated using qPCR, western blotting and in situ PLA. We additionally observed significantly accelerated proliferation in islets from young heterozygous animals.

It is often problematic to determine prognosis for individual patients with PNET. This is especially true in the group of patients with well differentiated endocrine carcinomas. In the absence of metastases, morphological signs of malignancy are frequently lacking. We evaluated the expression of nuclear and cytoplasmic survivin in a clinically characterized patient material (n=111), and a high nuclear survivin expression proved to be a significant negative prognostic factor for survival.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 69 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 792
Keyword
MEN 1, PNET, tumor development, haploinsufficiency, survivin
National Category
Cancer and Oncology Endocrinology and Diabetes
Research subject
Endocrinology and Diabetology
Identifiers
urn:nbn:se:uu:diva-175033 (URN)978-91-554-8415-6 (ISBN)
Public defence
2012-09-28, Enghoffsalen, Ingång 50, Akademiska Sjukhuset, UPPSALA, 13:15 (English)
Opponent
Supervisors
Available from: 2012-08-31 Created: 2012-05-31 Last updated: 2013-01-22Bibliographically approved

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Halin Lejonklou, MargaretaSkogseid, Britt

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