摘要：

GATA TRANSCRIPTION FACTORS IN THE DEVELOPMENT AND TUMORS OF THE ADRENAL CORTEX Sanne Kiiveri Pediatric Graduate School Hospital for Children and Adolescents and Program for Developmental and Reproductive Biology Biomedicum Helsinki University of Helsinki Finland ACADEMIC DISSERTATION To be publicly discussed with the permission of the Medical Faculty of the University of Helsinki, in the Niilo Hallman Auditorium of the Hospital for Children and Adolescents, on October 22nd, 2004, at 12 noon Helsinki 2004 Supervisor Professor Markku Heikinheimo Hospital for Children and Adolescents University of Helsinki Helsinki, Finland Reviewers Docent Pivi Tapanainen Department of Pediatrics University of Oulu Oulu, Finland and Docent Maija Wessman Finnish Genome Center and Folkhlsan Research Center, University of Helsinki Helsinki, Finland Official opponent Professor Jorma Toppari Departments of Physiology and Pediatrics University of Turku Turku, Finland ISBN 952-91-7766-6 (paperback) ISBN 952-10-2076-8 (PDF) http://ethesis.helsinki.fi Yliopistopaino Helsinki 2004 To My Family CONTENTS CONTENTS SUMMARY ORIGINAL PUBLICATIONS ABBREVIATIONS INTRODUCTION REVIEW OF THE LITERATURE Development and function of the adrenal gland Fetal period Postnatal period Steroidogenesis Regulatory factors in the adrenal cortex Regulation of gene expression Steroidogenic factor 1 and DAX-1 Other transcription factors Hormones Growth factors Tumors of the mouse adrenal cortex Inbred mouse strains Transgenic mouse models Human adrenocortical tumors Incidence Clinical and histological features Molecular mechanisms GATA family of transcription factors Common features of the GATA proteins GATA-1, GATA-2 and GATA-3 are expressed in hematopoietic cells Important roles for GATA-4 in heart and gonads GATA-5, a less essential family member Several tissues express GATA-6 Friends of GATA; important cofactors for GATA proteins AIMS OF THE STUDY 4 6 8 9 10 12 12 12 14 15 17 17 17 18 20 22 22 22 23 24 24 25 26 27 27 29 30 32 33 34 35 CONTENTS MATERIALS AND METHODS Normal and transgenic mouse tissues (I-III) Human tissues: clinical and histological data (I, II, IV) Cell lines and stimulations (I, III, IV) Reverse-transcriptase polymerase chain reaction (II, III, IV) Northern blot analysis (I-IV) RNAse protection assay (I) RNA in situ hybridization (I-III) Immunohistochemistry and immunocytochemistry (I-IV) Electrophoretic mobility shift assay (III) Transient transfection assay and siRNA experiments (III) Statistical analysis (I, III, IV) Ethical considerations (I-IV) 36 36 36 37 38 38 39 40 40 41 42 42 42 RESULTS AND DISCUSSION GATA-4 is predominantly expressed in the fetal adrenal gland (I-II) GATA-6 is expressed in the fetal and adult adrenal gland (I-II) Regulation of GATA-4 and GATA-6 expression (I, III) GATA transcription factors in the endocrine organs (I-IV) Reciprocal changes in GATA-4 and GATA-6 expression in hormonally induced mouse adrenocortical tumors (I, III) Relationship between GATA-4 and luteinizing hormone receptor in mice (I, IV) GATA-4 is also expressed in a proportion of human adrenocortical tumors (I, IV) GATA-6 expression is diminished in human adrenocortical carcinomas (IV) 43 43 46 48 50 52 55 57 58 CONCLUSIONS AND FUTURE PERSPECTIVES ACKNOWLEDGEMENTS REFERENCES 61 63 65 5 SUMMARY SUMMARY The adrenal cortex is part of the hypothalamic-pituitary-adrenal axis and has vital roles in the regulation of intrauterine homeostasis, postnatal glucose and electrolyte balance and in stress response. Although some of the essential factors during these events have been identified, regulation of the development and function of the adrenal cortex is still not fully understood. Little is also known about the molecular events leading to adrenocortical tumorigenesis. The GATA family of transcription factors consists of six conserved zinc finger proteins expressed with distinct developmental and tissue-specific profiles. Transcription factors GATA-4 and GATA-6 are essential during early embryogenesis, and have roles in the development and function of several organs

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