REGULATION OF MALE GERM CELL APOPTOSIS Roles of sex steroids and the cellular death receptors Fas and TNFR1

...................................................................................................................................... 8 INTRODUCTION ........................................................................................................................ 10 REVIEW OF THE LITERATURE ..................................................................................... 11 Spermatogenesis .............................................................................................................. 11 Development of the testis .................................................................................................... 11 Adult spermatogenesis ......................................................................................................... 11 Apoptotic cell death in the testis .................................................................................... 14 Apoptosis ............................................................................................................................... 14 Caspase activation .................................................................................................... 14 Intracellular regulators of apoptosis ...................................................................... 15 Caspase-independent apoptosis .............................................................................. 17 Germ cell apoptosis ............................................................................................................... 18 Physiological germ cell apoptosis ........................................................................... 18 Inappropriate germ cell apoptosis .......................................................................... 18 Hormonal control of germ cell apoptosis ............................................................................. 19 Gonadotropins and androgens ................................................................................ 19 Estrogens ..................................................................................................................... 20 Apoptosis control by the death receptors Fas and TNFR1 ................................... 21 Death receptors and ligands ................................................................................................ 21 Mechanisms for the regulation of apoptosis by Fas and TNFR1 .................................... 22 Physiological roles of the FasLand TNFαinduced signaling ..................................... 24 The Fas system in the testis ................................................................................................. 25 Testicular production and effects of TNFα ........................................................................ 25 Nuclear factor κB (NF-κB) ................................................................................... 26 NF-κB/Rel and IκB proteins ................................................................................................. 26 Activation and target genes of NF-κB ................................................................................. 26 Regulation of apoptosis by NF-κB ...................................................................................... 28 NF-κB in the testis ................................................................................................................. 28 AIMS OF THE STUDY ............................................................................................................. 30 MATERIALS AND METHODS Patients ....................................................................................................................................... 31 Tissue culture and treatments ............................................................................................... 31 Laboratory analyses ........................................................................................ 31 Southern blot analysis of DNA fragmentation .................................................................. 31