SuperMEN1 (eBook)

Katalin Balogh, MD, PhD: I graduated from Semmelweis University, Budapest as a Medical Doctor in 2001 and defended my PhD thesis on the clinical and genetic aspects of multiple endocrine neoplasia Type 1 in 2007. Working as a student at the Department of Physiology, then as a physician at the 2nd Department of Medicine, Semmelweis University, Budapest, I always had the inspiration to build bridges between patients, clinicians and researchers. Being a part of connecting different fields of medicine has always been and still remains a challenge for me. My main research interest is endocrine oncology. I am a member of the Endocrine Society and an international scholarship has afforded me the opportunity to work as a research fellow in Toronto. I hope to continue to build connections between people, continents and nations. Attila Patocs MD, MSc, PhD: I completed my medical and PhD training at Semmelweis University, Budapest, Hungary in 1998 and 2005, respectively. My interest has always focused on experimental laboratory work; therefore I attended and completed a biomedical engineering training at the Budapest Technical University in 2000. Between 2005-2007 I participated in a two-year postdoctoral fellowship in Dr. Charis Eng’s laboratory at the Comprehensive Cancer Center of the Ohio State University and at the Genomic Medicine Institute of the Cleveland Clinic. Back in my home country from 2008 I am head of the Central Isotope Diagnostic Laboratory at the Semmelweis University and as a research associate I am working with the Molecular Medicine Research Group of the Hungarian Academy of Sciences. My research focuses on genetic and genomic characterization of endocrine tumors, on understanding of glucocorticoid signaling and on development of new, routine and molecular biological laboratory methods for diagnosis of endocrine disorders.

PREFACE 6
ABOUT THEEDITORS... 7
ABOUT THE EDITORS... 8
PARTICIPANTS 9
Table Contents 11
ACKNOWLEDGEMENTS 14
CHAPTER 1 MENl Clinical Background 15
Abstract 15
Introduction 15
Clinical Features 16
Diagnosis of MEN1 20
MEN1 Variants and Phenocopy 20
Diagnostics of MEN1-Related Tumors 22
HPT 22
Pancreatic Islet Tumors 22
Laboratory Diagnosis 22
Imaging 22
Pituitary Tumors 22
Adrenal Tumors 23
Carcinoid Tumors 23
Nonendocrine Tumors 23
Screening for MEN1 Manifestations 23
Indications for MEN1 Germline Mutation Screening 23
Therapy 25
Hyperparathyroidism 25
Endocrine Pancreas Tumors 25
Pituitary Tumors 26
Surveillance 26
Comments and Conclusion 26
References 27
CHAPTER 2 Genetic Background of MEN1: From Genetic Homogeneity to Functional Diversity 30
Abstract 30
Introduction: The History of a Rare Endocrine Genetic Disease 30
On the Nature of the MEN1 Gene 31
What Do We Learn from the Hereditary Mutations of the MEN1 Gene? 34
Importance of MEN1 in Endocrine Tumorigenesis 34
Is MEN1 a Genome Instability Syndrome? 35
Conclusion 36
Acknowledgements 36
References 37
CHAPTER 3 Menin: The Protein Behind the MEN1 Syndrome 40
Abstract 40
Introduction 40
Menin Is a Nuclear Protein-Role of the C-Terminal Region 40
Leucine-Rich Domains in Menin 42
GTPase Signature Motif 43
Post-Translational Modification in Response to DNA Damage 43
Conservation ofMenin Structure, Protein Interactions and Function 43
Conclusion 46
Acknowledgements 47
References 47
CHAPTER 4 Cellular Functions of Menin 50
Abstract 50
Introduction 50
Cell Cycle 50
Menin andthe Cell Cycle 51
Menin andthe Retinoblastoma Protein 51
Menin and CDK Inhibitors 51
Menin and GTPases 53
Menin and]unD 53
Menin and Activator DIS-Phase Kinase (ASK) 54
Menin and TGF- ß Family Members 54
Cell CycleCheckpoints and DNA Repair 56
Menin and Genomic Instability 56
Menin, DNA Binding and ATR-CHKl Pathway 56
Menin and FANCD2 58
Menin and RPA2 58
Menin and FOXN3 (CHES1) 58
Chromatin Remodeling 58
Menin and Transcriptional Regulation 58
Menin and Histone Deacetylase 58
Menin and Histone Methyltransferase 60
Menin, Chromatin and Gene Expression 60
Conclusion 60
Acknowledgements 60
References 61
CHAPTER5 The Role of Menin in Hematopoiesis 64
Abstract 64
Introduction 64
Menin Is Associated with MLL, a Histone Methyltransftrase Rearranged in Leukemia 64
Role of Menin in Hematopoiesis 66
Role of Menin in Leukemogenesis 67
Conclusion 68
References 69
CHAPTER 6 Role of Menin in Bone Development 71
Abstract 71
Introduction 71
Menin and TGF- ß Signaling 71
Menin and AP-1 Signaling 72
BMP, TGF- ß and AP-1 Signaling in the Osteoblast 72
Role of Menin in Early Stage Osteoblast Differentiation 74
Menin and TGF- ß Pathway in Osteoblast Differentiation 74
Menin and JunD in the Osteoblast 76
Conclusion 77
Acknowledgements 78
References 78
CHAPTER 7 Activin, TGF- ß and Menin in Pituitary Tumorigenesis 80
Abstract 80
Introduction 80
Genetics of Pituitary Adenomas: Role of MEN1 Mutations 81
'The Activin/TGF-B Superfamily 82
Activin/TGF- ß in the Pituitary 83
Activin Inhibits Prolactin Gene Expression and Signalling 83
Menin Inactivation 84
Loss of Menin Inhibits TGF- ß Induced Transcriptional Activity 84
Menin Interacts with Smad Proteins 84
Smads and Menin Are Required for Activin-Mediated Cell GrowthInhibition and Repression of Prolactin Gene Expression 85
Conclusion 86
Acknowledgements 86
References 86
CHAPTER 8 The Role of Menin in Parathyroid Tumorigenesis 90
Abstract 90
Introduction 90
The MEN1 Gene 90
MEN1 Related Mutations and Menin Expression in Hereditary and Sporadic Hyperparathyroidism (Genotype-Phenotype Correlation) 93
TGF- ß /Smad3 Signalling 94
Menin and TGF- ß Signalling 94
Other Forms of Parathyroid Tumorigenesis 96
Conclusion 96
References 96
CHAPTER 9 Role of Menin in Neuroendocrine Tumorigenesis 98
Abstract 98
Introduction 98
Global Gene Expression in Normal Islet Cells versus MEN 1-Associated Neuroendocrine Tumors 99
Signaling Pathways in Neuroendocrine Tumors 101
ASCLI 101
NotchI 102
Raj-1 103
Treatment of Neuroendocrine Tumors Based on Molecular Genetic Diagnosis 103
References 104
CHAPTER 10 Adrenal Tumors in MEN1 Syndrome and the Role of Menin in Adrenal Tumorigenesis 107
Introduction 107
Genetics of Adrenal Tumors 107
Hereditary Syndromes with Adrenal Involvement 107
Somatic Genomics ofSporadic Adrenal Tumors 108
MEN1-Associated Adrenal Tumors 109
Prevalence 109
ClinicalFeatures 109
Diagnosis, Therapy and Follow-Up of Adrenal Tumors 110
Localization 110
Laboratory Diagnosis 110
Therapy 110
Follow-Up 111
MEN] Gene Mutation Screening in Patients with Adrenal Tumors: To Screen or Not? 111
Comments and Conclusion 112
References 112
CHAPTER 11 Functional Studies of Meninthrough Genetic Manipulation of the Men1 Homolog in Mice 114
Abstract 114
Introduction 114
Conventional Men1 Mouse Models 115
Conditional Men1 Mouse Mutants 117
Pancreas and Pituitary 118
Parathyroid 118
Liver 118
LeukemicPrecursor CellsandNormalBoneMarrow 119
Neural Crest 119
Menin Overexpression 119
Crossbreeding Studies 120
Conclusion 121
Acknowledgements 123
References 123
INDEX 125