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De androgeenreceptor is een transcriptiefactor. AR. Androgens. A. A. Δ Gene expression. Androgens. Testosterone Dihydrotestosterone. Androgens affect: - Embryologic development - Bone and muscle - Male puberty - Behaviour
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AR Androgens A A ΔGene expression
Androgens Testosterone Dihydrotestosterone Androgens affect: - Embryologicdevelopment - Bone and muscle - Male puberty - Behaviour - Reproduction - Prostate & PrCa - Osteoporosis and frailty
AR Androgens A A ΔGene expression
Gene regulationbytestosterone • Testosteron binds the androgen receptor • The receptor binds DNA • The receptor activates gene expression • Therapies
The receptor bindstestosterone AR: LBD AF2 DBD AF1 Gene activation DNA binding Ligand-binding
+ ligand H9 H8 H1 H4 H5 H10 H7 H12 T H2 H11 H3 6 W Effect of testosterone binding no ligand H9 H8 H1 H4 H5 H10 S1 H7 LxxLL H3 S2 H2 6 H11 W H12
Gene regulationbytestosterone • Testosteron activates the androgen receptor • The receptor binds DNA • The receptor activates gene expression • Therapies
The DNA-binding domain of the AR AR: LBD AF2 DBD AF1
How does testosterone affect gene expression? Ligand-binding AR: Gene activation DNA binding LBD AF2 DBD AF1
Gene regulationbytestosterone • Testosteron binds the androgen receptor • The receptor binds DNA • The receptor activates gene expression
Histon code and testosteron action AR: LBD AF2 DBD Tau-1 Tau-5 Chromatin-remodeling complex p160 TIF1β TFIIF CBP, P/CAF CARM1 Histon code recognition erasing RNApol II recruitment expression Histon code writing
Testosteron effectson the histon code: a cartoon RNA polII -p160 AR AR -CRC AR AR -TFIIF -TIF1b
The DBD and LBD communicate AR: Transactivation DNA binding Ligand-binding LBD AF2 DBD Tau-1 Tau-5 Cycling partners Cyclinghiston code
Gene regulationbytestosterone • 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 A SNP2 T TM-ARE2 SNP1 SNP2
Two SNPs in TM-ARE2 Chr 21 SNP1 A SNP2 T TM-ARE2 WT SNP1 SNP2
Mol Endo Lab • AR stuctuur en functie • PrCaresistentietegenAR antagonisten • Nieuwe AR antagonisten • PrCagenomen en diagnostischemerkers • SNPs • Frailty: osteoporosis