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Progesterone Receptors

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Progesterone Receptors SCUOLA DI DOTTORATO Medicina Sperimentale e Biotecnologie Mediche XXIX Ciclo DIPARTIMENTO Biotecnologie Mediche e Medicina Traslazionale TESI DI DOTTORATO DI RICERCA Effects of 3-ketodesogestrel and all-trans retinoic acid on PHOX2A and PHOX2B expression: a common strategy as new therapeutic perspective in Congenital Central Hypoventilation Syndrome (CCHS) and Neuroblastoma (NB) treatment. settore scientifico disciplinare: Bio/14 NOME DEL DOTTORANDO Debora Belperio NOME E COGNOME DEL TUTOR Prof. Diego Fornasari NOME E COGNOME DEL COORDINATORE DEL DOTTORATO Prof. Massimo Locati A.A. 2016/2017 1 Contents Abbreviations: ............................................................................................................................................... 4 Abstract ......................................................................................................................................................... 5 CHAPTER 1 ..................................................................................................................................... 7 General introduction .................................................................................................................................. 7 1.1 Phox2 proteins in nervous system development .................................................................................... 8 1.2 Phox2b and the brainstem respiratory circuit ...................................................................................... 12 1.3 PHOX2 proteins in normal condition: structure and function .............................................................. 16 1.4 PHOX2 proteins and disease: ................................................................................................................ 19 Neuroblastoma and Genetic disorders ....................................................................................................... 19 1.4.1 Neuroblastoma .................................................................................................................................. 20 Genetic basis of NB ............................................................................................................................ 20 PHOX2B pathogenetic mechanisms in NB .......................................................................................... 21 Pharmacological research in NB ......................................................................................................... 23 1.4.2 PHOX2 proteins in genetic disorders ................................................................................................. 25 Congenital fibrosis of the extraocular muscles type 2 (CFEOM2) .......................................................... 25 Congenital Central Hypoventilation Syndrome (CCHS) .......................................................................... 26 Genetic basis of CCHS ......................................................................................................................... 28 Pathogenetic mechanisms in CCHS .................................................................................................... 30 Therapeutic approach in CCHS treatment: ............................................................................................. 32 Aggregates targeting approach .......................................................................................................... 32 The progestin desogestrel: from bedside to bench side ........................................................................ 35 - Progesterone receptors ................................................................................................................... 38 - Classical nuclear progesterone receptors (cPRs) ............................................................................. 39 - Membrane progesterone receptors (mPRs) .................................................................................... 42 Progesterone: genomic and non-genomic mechanism ...................................................................... 43 Aim of the thesis: ........................................................................................................................................ 46 CHAPTER 2 .................................................................................................................................. 49 Alanine Expansions Associated with Congenital Central Hypoventilation Syndrome Impair PHOX2B Homeodomain-mediated Dimerization and Nuclear Import ..................................................................... 49 CHAPTER 3 .................................................................................................................................. 53 PHOX2A and PHOX2B are differentially regulated during retinoic acid driven differentiation of SK-N- BE(2)C neuroblastoma cell line ................................................................................................................. 53 CHAPTER 4 .................................................................................................................................. 57 3-ketodesogestrel effects in SK-N-BE(2)C neuroblastoma cell lines stably expressing human progesterone receptors (hPGR) ...................................................................................................................................... 57 2 4.1 Preliminary data ................................................................................................................................. 58 4.2 Material and methods......................................................................................................................... 63 Cell cultures ................................................................................................................................................. 64 Transient Transfections and Luciferase Assays ........................................................................................... 64 Plasmids used: ............................................................................................................................................. 65 Expression plasmids: ............................................................................................................................... 65 Reporter constructs: ............................................................................................................................... 65 Total protein extraction .............................................................................................................................. 66 SDS-PAGE and Western blot ....................................................................................................................... 67 RNA extraction ............................................................................................................................................ 69 Retrotranscription ....................................................................................................................................... 69 Quantitative Real-Time PCR ........................................................................................................................ 70 4.3 Results ................................................................................................................................................ 71 4.3.1 PHOX2B binding to "ATTA" consensus sequences on TLX2 promoter is necessary for the 3-KDG effects ......................................................................................................................................................... 72 4.3.2 3-KDG treatment increases the PHOX2B protein amount in T47D cell line ....................................... 75 4.3.3 Analyses of the endogenous nuclear progesterone receptor level in neuroblastoma cell lines ....... 76 4.3.4 3-KDG treatment alters the TLX2 promoter activity in neuroblastoma cell lines .............................. 78 4.3.5 3-KDG treatment does not alter PHOX2B / PHOX2A mRNA levels in SK-N-BE(2)C cell line transiently overexpressing human PGR. ....................................................................................................................... 80 4.3.6 3-KDG treatment induces a decrement in PHOX2B protein amount in SK-N-BE(2)C cell line transiently overexpressing human PGR. ..................................................................................................... 83 4.3.7 Effect of 3-KDG in SK-N-BE(2)C cell lines stably over-expressing human progesterone receptors.... 86 4.3.8 Effect of 3-KDG on endogenous PHOX2A, PHOX2B TLX2 and DBH transcript levels in SK-N-BE(2)C cell line stably over-expressing PR-B and PR-a progesterone receptors. .......................................................... 89 CHAPTER 5 .................................................................................................................................. 92 General discussion .................................................................................................................................... 92 Conclusion ............................................................................................................................................ 100 Acknowledgment ...................................................................................................................................... 101 Bibliography .............................................................................................................................................
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