Gene activation AF1 LBD AF2 AR
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De androgeenreceptor is een transcriptiefactor Androgens A A Δ Gene expression AR Androgens Testosterone Dihydrotestosterone Androgens affect: - Embryologic development - Bone and muscle - Male puberty - Behaviour - Reproduction - Prostate & PrCa - Osteoporosis and frailty Androgens A A Δ Gene expression AR Gene regulation by testosterone Testosteron binds the androgen receptor The receptor binds DNA The receptor activates gene expression Therapies The receptor binds testosterone AR: AF1 Gene activation DBD DNA binding LBD AF2 Ligand-binding Testosterone binds the receptor Effect of testosterone binding H9 H9 H8 H5 H8 H5 H1 + ligand H7 H10 no ligand H4 H4 H1 S1 H2 S2 H3 6 T 6 W W H2 H3 Gene regulation by testosterone Testosteron activates the androgen receptor The receptor binds DNA The receptor activates gene expression Therapies The DNA-binding domain of the AR AR: AF1 DBD LBD AF2 How does testosterone affect gene expression? AR: Gene activation AF1 DBD DNA binding LBD AF2 Ligand-binding Gene regulation by testosterone Testosteron binds the androgen receptor The receptor binds DNA The receptor activates gene expression Histon code and testosteron action AR: Tau-1 Tau-5 DBD LBD AF2 Chromatin-remodeling complex p160 TIF1β TFIIF Histon code recognition erasing RNApol II recruitment expression Histon code writing Testosteron effects on the histon code: a cartoon AR -p160 AR -CRC AR -TFIIF AR-TIF1b The DBD and LBD communicate AR: Tau-1 Transactivation Cycling partners Cycling histon code Tau-5 DBD DNA binding LBD AF2 Ligand-binding Gene regulation by testosterone Testosteron binds the androgen receptor The receptor binds DNA The receptor activates gene expression Prostate cancer New markers in prostate cancer 6,6 x 109 bp: A,C,G or T 107 Single nucleotide polymorphisms Gene fusions Gene fusions in PCa CTRL : Oncogenes 50% ! Two SNPs in the TM-enhancer Chr 21: TMPRSS2 gene SNP1 SNP2 A T TM-ARE2 SNP1 SNP2 Two SNPs in TM-ARE2 Chr 21 TM-ARE2 SNP1 SNP2 A T WT SNP1 SNP2 Relevance of TM-ARE2 SNPs? Mol Endo Lab • • • • • • AR stuctuur en functie PrCa resistentie tegen AR antagonisten Nieuwe AR antagonisten PrCa genomen en diagnostische merkers SNPs Frailty: osteoporosis