German Title: Die Rolle von Men1 in Hypophysen Tumorigenese

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Abstract

Summary The pituitary gland is a key regulator of growth, metabolism and sexual development. The pituitary gland integrates signals from the hypothalamus and from peripheral endocrine glands and responds to changing physiological needs by secreting a series of hormones that regulate the activity of various endocrine glands as well as acting directly on many tissues. Tumours of the pituitary gland are relatively frequent possibly due to the plasticity of the gland. Pituitary gland tumours occur both sporadically and as part of inherited multiple endocrine neoplasia (MEN) syndromes. MEN1 is one of these inherited syndromes. People suffering from MEN1 develop tumours of the pituitary gland, the parathyroid glands, the pancreatic islets and the adrenal glands. MEN1 is caused by a loss of function mutation in the tumour suppressor gene MEN1. Men1 expression is found in all tissues in the mouse and not only in the endocrine system. Menin the protein encoded by Men1, shares no homology with any known proteins and contains no recognisable protein domains. Menin is believed to function as a regulator of transcription through binding to several specific transcription factors. These include Smad transcription factors, JunD and members of the NF-kB family of proteins. To investigate the phenotype of Men1 deficiency and to elucidate the mechanism of MEN1 tumourigenesis I have generated a conditional Men1 mouse model that enables me to specifically delete Men1 in the pituitary gland. Men1 deficient pituitary glands are hyperplastic as early as 7 weeks of age. The hyperplasia often develops into massive adenomas by 40 weeks of age. Both hyperplasia and adenoma formation shows a gender difference and is more pronounced in female mice. Analysis of the Men1 deficient pituitary glands revealed pituitary gland overproliferation by 12 weeks of age before the development of adenomas. Microarray analysis of the Men1 deficient pituitaries identified two growth factors that were significantly overexpressed in Men1 deficient pituitary glands. Both of these factors also showed a clear gender difference in their expression levels. The overexpression of these growth factors in the Men1 deficient pituitaries was confirmed by in situ hybridisation.