1. De androgeenreceptor is een transcriptiefactor

2. Androgens AR Δ Gene expression A A

3. Androgens affect: - Embryologic development - Bone and muscle - Male puberty - Behaviour - Reproduction - Prostate & PrCa - Osteoporosis and frailty Androgens Testosterone Dihydrotestosterone

4. Androgens AR Δ Gene expression A A

5. Gene regulation by testosterone  Testosteron binds the androgen receptor  The receptor binds DNA  The receptor activates gene expression  Therapies

6. DNA binding Ligand-bindingGene activation AF1 LBD AF2 AR: DBD The receptor binds testosterone

7. Testosterone binds the receptor

8. Effect of testosterone binding H1 H2 H3 H4 H5 6 H7 H8 H9 H10 H11 H12 S1 S2  no ligand H9 H1 H2 H3 H4 H5 H7 H8 H10 H11 H12  6 T + ligand LxxLL

9. Gene regulation by testosterone  Testosteron activates the androgen receptor  The receptor binds DNA  The receptor activates gene expression  Therapies

10. The DNA-binding domain of the AR AF1 LBD AF2 AR: DBD

11. DNA binding Ligand-binding How does testosterone affect gene expression? Gene activation AF1 LBD AF2 AR: DBD

12. Gene regulation by testosterone  Testosteron binds the androgen receptor  The receptor binds DNA  The receptor activates gene expression

13. Histon code recognition erasing TIF1β Histon code and testosteron action CBP, P/CAF CARM1 Histon code writing p160 RNApol II recruitment expression TFIIF Tau-1 LBD AF2 AR: DBD Tau-5 Chromatin-remodeling complex

14. -CRC -TIF1b Testosteron effects on the histon code: a cartoon AR -p160 RNA polII -TFIIF

15. DNA binding Ligand-binding The DBD and LBD communicate Transactivation Tau-1 LBD AF2 AR: DBD Tau-5 Cycling partners Cycling histon code

16. Gene regulation by testosterone  Testosteron binds the androgen receptor  The receptor binds DNA  The receptor activates gene expression  Prostate cancer

17. 6,6 x 10 9 bp: A,C,G or T 10 7 Single nucleotide polymorphisms Gene fusions New markers in prostate cancer

18. Gene fusions in PCa CTRL : Oncogenes 50% !

19. Two SNPs in the TM-enhancer SNP2 SNP1 T A TM-ARE2SNP1SNP2 Chr 21: TMPRSS2 gene

20. Two SNPs in TM-ARE2 WTSNP1SNP2 TM-ARE2 SNP2 SNP1 T A Chr 21

21. Relevance of TM-ARE2 SNPs?

22. Mol Endo Lab AR stuctuur en functie PrCa resistentie tegen AR antagonisten Nieuwe AR antagonisten PrCa genomen en diagnostische merkers SNPs Frailty: osteoporosis