Nuclear Receptors and Multiple Endocrine Neoplasia ...

Nuclear Receptors and Multiple Endocrine Neoplasia type 1 (MEN1)

Koen Dreijerink

Dreijerink, Koen Marie Anton Nuclear Receptors and Multiple Endocrine Neoplasia type 1 (MEN1) Thesis Utrecht University, The Netherlands Cover: Menin amino acid sequence. Design: Geertje Dreijerink Printed by: Gildeprint Drukkerijen Printing of this thesis was financially supported by the UMC Utrecht, Novo Nordisk B.V., Ipsen Farmaceutica and Novartis Oncology. The research described in this thesis was funded by ZonMW (AGIKO 920-03-231) and the Netherlands Proteomics Centre. ISBN/EAN: 9789490122348

Nuclear Receptors and Multiple Endocrine Neoplasia type 1 (MEN1)

Nucleaire Receptoren en Multipele Endocriene Neoplasie type 1 (MEN1) (met een samenvatting in het Nederlands)

Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof.dr. J.C. Stoof, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op donderdag 25 juni 2009 des middags te 2.30 uur door Koen Marie Anton Dreijerink geboren op 30 juli 1977 te Nijmegen

Promotoren:

Prof.dr. H.Th.M. Timmers Prof.dr. C.J.M. Lips

Contents Abbreviations………………………………………………………………...... 6 Chapter 1………………………………………………………………………..7 General introduction Chapter 2………………………………………………………………………. 27 Menin links estrogen receptor activation to histone H3K4 trimethylation Chapter 3………………………………………………………………………. 43 The Multiple Endocrine Neoplasia type 1 (MEN1) tumour suppressor regulates PPARγ-dependent adipocyte differentiation Chapter 4………………………………………………………………………. 65 Structural and functional properties of the Multiple Endocrine Neoplasia type 1 (MEN1) gene product, menin Chapter 5………………………………………………………………………..77 Regulation of vitamin D receptor function in Multiple Endocrine Neoplasia type 1 (MEN1)-related parathyroid adenomas Chapter 6………………………………………………………………………. 93 General discussion and future implications Summary………………………………………………………………………..102 Samenvatting………………………………………………...………………... 103 Dankwoord…...………………………………………………………………... 105 Curriculum vitae……………………………………………………..………… 108 List of publications………………………………………………..…………… 109

Abbreviations AQP7 Ash2 ATP CDKI ChIP DNA FABP ER ERE H3K4me3 HAT HDAC HMT LEDGF MEF MEN MLL mRNA NR PCR Pol II PPAR PPRE RBBP RNA RT RXR SET siRNA TAF TBP UAS VDR WDR5

Aquaporin 7 Absent, small or homeotic discs 2 Adenosine 5’-triphosphate Cyclin-dependent kinase inhibitor Chromatin Immunoprecipitation Deoxyribonucleic acid Fatty acid binding protein Estrogen receptor Estrogen responsive element Histone H3 lysine 4 trimethylation Histone acetyl transferase Histone deacetylase Histone methyltransferase Lens epithelium-derived growth factor Mouse embryonic fibroblast Multiple endocrine neoplasia Mixed-lineage leukemia Messenger ribonucleic acid Nuclear receptor Polymerase chain reaction RNA polymerase II Peroxisome proliferator activated receptor PPAR responsive element Retinoblastoma binding protein Ribonucleic acid Reverse transcriptase Retinoid X receptor Su(var)3-9, Enhancer of Zeste and Trithorax Small interfering ribonucleic acid TBP-associated factor TATA binding protein Upstream activating sequence Vitamin D receptor WD repeat domain 5

6

Chapter 1 General introduction

Chapter 1: General introduction

OMIM 171400, MEN2B-OMIM 162300) frequently develop medullary thyroid carcinoma and pheochromocytoma. MEN2 is caused by activating germ line mutations of the RET proto14 oncogene. Very recently, two independent reports were published on families with parathyroid adenomas and pituitary adenomas. In these patients, germ line mutations of the MEN1 gene could not be detected. However, germ line mutations in the 18,19 CDKN1B gene were identified. This disease has been named MEN4 (OMIM 610755).

1.1. Clinical manifestations of Multiple Endocrine Neoplasia type 1 (MEN1) History of Multiple Endocrine Neoplasia In 1903, Jakob Erdheim, a pathologist from Vienna, described the case of a 42-year-old acromegalic patient with a pituitary adenoma, aortic valve insufficiency and left ventricle hypertrophy, necrosis of the pancreas 1 and three enlarged parathyroid glands. In retrospect, his report is probably the first on a patient with a condition we nowadays refer to as Multiple Endocrine Neoplasia. In 1927, Cushing and Davidoff reported the finding of two parathyroid adenomas, a pancreatic adenoma, a lipoma and adenomas of both adrenal glands at autopsy also in a patient with acromegaly caused by a 4 pituitary adenoma. In the 1950’s Underdahl et al. and Wermer et al. were among the first to recognise that the syndrome was transmitted in an 6,7 autosomal dominant fashion. Steiner introduced the term Multiple Endocrine Neoplasia in 1968, and renamed Wermer’s syndrome to Multiple 11, Endocrine Neoplasia type 1 (MEN1). 12 1 Besides MEN1 (OMIM 131100), two other distinct MEN syndromes exist. Patients with multiple endocrine neoplasia type 2 (MEN2; MEN2A1

Manifestations of MEN1 Multiple endocrine neoplasia type 1 (MEN1) is an inherited disease that is characterised by the occurrence of multiple tumours in multiple endocrine organs, often at a young age. The most common manifestations of MEN1 include parathyroid adenomas, gastroenteropancreatic tumours, pituitary adenomas, adrenal cortical adenomas as well as neuro-endocrine tumours of the thymus, the lungs and 21 the stomach (listed in Table 1.1). Collagenomas, leiomyomas, angiofibromas, lipomas and meningiomas are nonclassical endocrine features of 4,24,25 MEN1. The prevalence of MEN1 is about 2-3 per 100,000 individuals, and is equal among males and females. It is estimated that in the Netherlands there are about 400 MEN1 patients.

Online Mendelian Inheritance in Man (OMIM).

Online database of inherited disorders. Johns Hopkins University, Baltimore, MD. World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim/

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Chapter 1: General introduction

Parathyroid adenomas

Disease morbidity of MEN1 among affected individuals is high. More than 90% of MEN1 patients develop 21 parathyroid adenomas. Parathyroid tumours are often the first manifestation of MEN1, most MEN1 patients have developed hyper28 parathyroidism at age 50. Usually, MEN1-associated parathyroid adenomas are benign. Approximately 70% of patients develop tumours of the gastroenteropancreatic tract, most often gastrin or insulin-producing tumours (gastrinomas and insulinomas) 30 or nonfunctioning tumours. Approximately 40% of patients develop pituitary adenomas, mostly prolactinproducing tumours or non-functioning 21 tumours. MEN1-associated tumours may cause symptoms due to excessive hormone production, for example fatigue or nausea due to hypercalcaemia in hyperparathyroidism. Alternatively, symptoms can be caused by tumour expansion, for example a pituitary adenoma causing a visual field defect. Treatment of MEN1 tumours is dependent on the tumour type. Most tumours in MEN1 are benign and can be treated efficiently by surgery or by drugs. Thymic carcinoids, although rare, have a malignant course and are very often lethal, as it appears to be impossible to treat these tumours 34,35 curatively. Gastrin-producing tumours in the duodenum or pancreas can also pose a significant threat,

90–99%

Gastroenteropancreatic tumours

65–75%

Gastrinomas

45%

Insulinomas

10%

Non-functioning 10% Other

2%

Pituitary adenomas

30–65%

Prolactinomas

30%

Non-functioning 10% ACTH-producing 1% GH-producing

3–6%

Adrenal adenomas

16–37%

Carcinoid tumours

18%

Thymus

8%

Bronchial

8%

Stomach

7%

Skin lesions

80%

Angiofibromas

75-85%

Collagenomas

5-70%

Lipomas

30%

Leiomyomas

5%

Meningiomas