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Molecular Biology of the Parathyroid - Tally Naveh-Many

Contents


1. Development of Parathyroid Glands ...................................................... 1
Thomas G√ľnther and Gerard Karsenty
Physiology of the Parathyroid Glands .................................................... 1
Development of Parathyroid Glands in Vertebrates ............................... 1
Genetic Control of Parathyroid Gland Development ............................ 3
2. Parathyroid Hormone, from Gene to Protein ........................................ 8
Osnat Bell, Justin Silver and Tally Naveh-Many
The Prepro PTH Peptide ...................................................................... 8
Homology of the Mature PTH ............................................................. 9
The PTH mRNA ................................................................................ 10
Cloning of the PTH cDNAs ............................................................... 11
Homology of the cDNA Sequences ..................................................... 12
Structure of the PTH mRNA .............................................................. 18
The PTH Gene ................................................................................... 21
The 5’ Flanking Region ....................................................................... 24
The 3' Flanking Region ....................................................................... 24
Chromosomal Location of the Human PTH Gene ............................. 25
3. Toward an Understanding of Human Parathyroid
Hormone Structure and Function ........................................................ 29
Lei Jin, Armen H. Tashjian, Jr., and Faming Zhang
PTH and Its Receptor Family ............................................................. 29
PTH Structural Determination ........................................................... 30
Structural Based Design of PTH Analogs ............................................ 37
4. The Calcium Sensing Receptor ............................................................ 44
Shozo Yano and Edward M. Brown
Biochemical Characteristics of the CaR ............................................... 45
Disorders Presenting with Abnormalities in Calcium
Metabolism and in the CaR ............................................................ 47
Signaling Pathways of the CaR ............................................................ 49
Drugs Acting on the CaR .................................................................... 50

5. Regulation of Parathyroid Hormone mRNA Stability
by Calcium and Phosphate ................................................................... 57
Rachel Kilav, Justin Silver and Tally Naveh-Many
Regulation of the Parathyroid Gland by Calcium
and Phosphate ................................................................................. 57
Protein Binding and PTH mRNA Stability ......................................... 58
Identification of the PTH mRNA 3’-UTR Binding
Proteins and Their Function ........................................................... 61
Identification of the Minimal cis Acting Protein Binding
Element in the PTH mRNA 3’-UTR .............................................. 62
The Structure of the PTH cis Acting Element ..................................... 64
6. In Silico Analysis of Regulatory Sequences in the Human
Parathyroid Hormone Gene ................................................................. 68
Alexander Kel, Maurice Scheer and Hubert Mayer
Global Homology of PTH Gene between Human
and Mouse ...................................................................................... 71
Computer Assisted Search for Potential Cis-Regulatory
Elements in PTH Gene ................................................................... 75
Phylogenetic Footprint: Identification of TF Binding Sites
by Comparison of Regulatory Regions of PTH Gene
of Different Organisms .................................................................... 78
Discussion ........................................................................................... 80
7. Regulation of Parathyroid Hormone Gene Expression
by 1,25-Dihydroxyvitamin D ............................................................... 84
Tally Naveh-Many and Justin Silver
Transcriptional Regulation of the PTH Gene
by 1,25(OH)2D3 .............................................................................. 84
Calreticulin and the Action of 1,25(OH)2D3
on the PTH Gene ........................................................................... 89
PTH Degradation ............................................................................... 90
Secondary Hyperparathyroidism and Parathyroid
Cell Proliferation ............................................................................. 90
8. Vitamin D Analogs for the Treatment of Secondary
Hyperparathyroism in Chronic Renal Failure....................................... 95
Alex J. Brown
Pathogenesis of Secondary Hyperparathyroidism in Chronic
Renal Failure ................................................................................... 95
Treatment of Secondary Hyperparathyroidism .................................... 96
Mechanisms for the Selectivity of Vitamin D Analogs ....................... 104
Future Perspectives ............................................................................ 109

9. Parathyroid Gland Hyperplasia in Renal Failure ................................ 113
Adriana S. Dusso, Mario Cozzolino and Eduardo Slatopolsky
Parathyroid Tissue Growth in Normal Conditions
and in Renal Failure ...................................................................... 114
Dietary Phosphate Regulation of Parathyroid Cell Growth
in Uremia ...................................................................................... 116
Vitamin D Regulation of Uremia- and High Phosphate-Induced
Parathyroid Cell Growth ............................................................... 120
Calcium Regulation of Uremia-Induced Parathyroid Growth ........... 123
10. Molecular Mechanisms in Parathyroid Tumorigenesis ....................... 128
Eitan Friedman
Oncogenes Involved in Parathyroid Tumor Development ................. 129
Tumor Suppressor Genes Involved in Parathyroid
Tumorigenesis ............................................................................... 130
Other Molecular Pathways Involved in Parathyroid
Tumorigenesis ............................................................................... 132
11. Molecular Genetic Abnormalities in Sporadic
Hyperparathyroidism ......................................................................... 140
Trisha M. Shattuck, Sanjay M. Mallya and Andrew Arnold
Implications of the Monoclonality of Parathyroid Tumors ................ 141
Molecular Genetics of Parathyroid Adenomas ................................... 142
Molecular Genetics of Parathyroid Carcinoma .................................. 151
Molecular Genetics of Secondary and Tertiary
Hyperparathyroidism .................................................................... 152
12. Genetic Causes of Hypoparathyroidism ............................................. 159
Rachel I. Gafni and Michael A. Levine
Disorders of Parathyroid Gland Formation ....................................... 159
Disorders of Parathyroid Hormone Synthesis or Secretion ................ 167
Parathyroid Gland Destruction ......................................................... 170
Resistance to Parathyroid Hormone .................................................. 171
13. Skeletal and Reproductive Abnormalities in Pth-Null Mice ............... 179
Dengshun Miao, Bin He, Beate Lanske, Xiu-Ying Bai,
Xin-Kang Tong, Geoffrey N. Hendy, David Goltzman
and Andrew C. Karaplis
Results ............................................................................................... 180
Discussion ......................................................................................... 188
Materials and Methods ...................................................................... 193
Index .................................................................................................. 197

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