Lauber-Biason
Fakultäten » Medizinische Fakultät » Kinderspital Zürich: Medizinische Klinik » Endokrinologie/Diabetologie, Abteilung » Prof. Dr. Eugen Schönle » Lauber-Biason
Completed research project
| Title / Titel | Determinants of Endocrine Development and Function: Focus on the Pituitary Gland and Steroidogenic Tissues | ||||
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| Abstract (PDF, 14 KB) | |||||
| Summary / Zusammenfassung | The goal of the present project is two fold: 1. To understand the molecular basis of human pituitary development by analyzing the structure of genes known to be involved in pituitary development in patients affected by combined or isolated pituitary hormone deficiency (CPHD). To reach this goal we already clarified the genomic structure of one possible candidates (LHX3) and collected DNA of several CPHD patients. If no mutation will be found in this gene other candidates genes such as ISL1 and HESX1 will be examined. This study is expected to provide information useful to new diagnostic and therapeutical approaches for complete and isolated pituitary hormone deficiency. 2. To gain some more insights in the regulation of determination and development of steroidogenic tissues. 2.1. Determination. We will focus on factors responsible for the formation and determination of the adrenal gland, such as SF-1/NR5A1. Molecular analysis of this factor in patients with congenital adrenal insufficiency is awaited to furnish an additional diagnostic tool for this disease and to contribute to the knowledge of the systems modulating steroidogenic tissue growth. 2.2. Development. We will focus on the modulation of the androgenic (17,20-lyase) activity of CYP17, the qualitative regulator of steroidogenesis. We already demonstrated that post-translational modification, in particular phosphorylation of CYP17 are essential for 17,20-lyase activity. While the physiological switch between infantile and adult adrenal steroidogenesis (adrenarche) is still unknown, we could show that the adipose-derived agent leptin selectively stimulates the 17,20-lyase activity of CYP17 in adrenal cells. Again, this stimulation appears to be dependent on the phosphorylation state of CYP17. Given the interactions in vivo and in vitro between leptin, estradiol and IGF-I and the fact that all three signal transduction pathways cross-talk via phosphorylation of common target proteins (e.g. MAPK), we plan to study the role of such cross-talk in the regulation of 17,20-lyase activity. It would be of great interest to analyze whether these pathways play any role in the onset and regulation of adrenarche and puberty and/or in the decline of sex hormones production in aging. As an alternative approach, the nature of the kinase(s) responsible for the phosphorylation of CYP17 will be clarified via a partner-search approach by means of yeast two-hybrid system. The identification and characterization of this kinase might also help to understand the pathophysiology of androgen excess in premature adrenarche and polycystic ovary disease. Also, clarification of mechanisms governing sex hormone production will provide possible targets for the treatment of hormone-dependent cancers. | ||||
| Publications / Publikationen | Biason A, Mantero F, Scaroni C, Simpson ER, Waterman MR (1991) Deletion within the CYP17 gene together with insertion of foreign DNA is the cause of complete combined 17Ą-hydroxylase/17,20-lyase deficiency in an Italian patient. Mol Endocrinol 5:2037-2045 Biason-Lauber A, Leibermann E, Zachmann M (1997) A single amino acid exchange in the putative redox partner binding site of P450c17 as cause of isolated 17,20-lyase deficiency. J Clin Endocrinol Metab 82: 3807-3812 Biason-Lauber A, Kempken B, Werder E, Forest MG, Einaudi S, Ranke MB, Matsuo N, Brunelli V, Schoenle E, Zachmann M. (2000) 17Ą-hydroxylase/17,20-lyase deficiency as a model to study enzymatic activity regulation: role of phosphorylation. J Clin Endocrinol Metab 85: 1226-1231 Biason-Lauber A, Zachmann M, Schoenle EJ (2000) Effect of leptin on CYP17 enzymatic activities in human adrenal cells: new insight in the onset of adrenarche. Endocrinology 141: 1446-1454 Di Cerbo A, Biason-Lauber A, Savino M, Piemontese MR, Di Giorgio A, Perona M, Savoia A (2002) Combined 17Ą-hydroxylase/17,20-lyase deficiency caused by Phe93Cys mutation in the CYP17 gene. J Clin Endocrinol Metab 87: 898-905Biason-Lauber A, Schoenle EJ (2000) Apparently normal ovarian differentiation in a prepubertal girl with transcriptionally inactive steroidogenic factor-1 (NR5A1/SF-1) and adrenocortical insufficiency. Am J Hum Genet 67:1563-1568Biason-Lauber A, Schmitt S, Betts D, Schoenle EJ (2000) Genomic structure, chromosomal localization and expression pattern of the human Lim-Homeobox 3 (LHX3) gene. Biochem Biophys Res Commun 274: 49-56 |
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| Keywords / Suchbegriffe | Sexual differentiation; Steroidogenesis; Adrenals | ||||
| Project leadership and contacts / Projektleitung und Kontakte |
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| Funding source(s) / Unterstützt durch |
SNF (Personen- und Projektförderung) |
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| Duration of Project / Projektdauer | Apr 2001 to Mar 2005 |