Post on 01-Apr-2015
De androgeenreceptor is een transcriptiefactor
Androgens
AR
Δ Gene expression
A
A
Androgens affect:
- Embryologic development - Bone and muscle- Male puberty- Behaviour- Reproduction- Prostate & PrCa- Osteoporosis and frailty
Androgens
Testosterone Dihydrotestosterone
Androgens
AR
Δ Gene expression
A
A
Gene regulation by testosterone
Testosteron binds the androgen receptor
The receptor binds DNA
The receptor activates gene expression
Therapies
DNA binding Ligand-binding Gene activation
AF1 LBD AF2 AR: DBD
The receptor binds testosterone
Testosterone binds the receptor
Effect of testosterone binding
H1
H2
H3
H4H5
6
H7
H8
H9
H10
H11
H12
S1
S2
W
no ligand
H9
H1
H2H3
H4H5
H7
H8
H10H11
H12
W
6T
+ ligand
LxxLL
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
AF1 LBD AF2 AR: DBD
DNA binding Ligand-binding
How does testosterone affect gene expression?
Gene activation
AF1 LBD AF2 AR: DBD
Gene regulation by testosterone
Testosteron binds the androgen receptor
The receptor binds DNA
The receptor activates gene expression
Histon code recognition
erasing
TIF1β
Histon code and testosteron action
CBP, P/CAF CARM1
Histon code writing
p160
RNApol IIrecruitmentexpression
TFIIF
Tau-1 LBD AF2 AR: DBDTau-5
Chromatin-remodeling complex
-CRC -TIF1b
Testosteron effects on the histon code: a cartoon
AR AR AR AR-p160
RNA polII
-TFIIF
DNA binding Ligand-binding
The DBD and LBD communicate
Transactivation
Tau-1 LBD AF2 AR: DBDTau-5
Cycling partnersCycling histon code
Gene regulation by testosterone
Testosteron binds the androgen receptor
The receptor binds DNA
The receptor activates gene expression
Prostate cancer
6,6 x 109 bp: A,C,G or T
107 Single nucleotide polymorphisms
Gene fusions
New markers in prostate cancer
Gene fusions in PCaCTRL : Oncogenes
50% !
Two SNPs in the TM-enhancer
SNP2SNP1
T A
TM-ARE2 SNP1 SNP2
Chr 21: TMPRSS2 gene
Two SNPs in TM-ARE2
WT SNP1 SNP2
TM-ARE2
SNP2SNP1
T A
Chr 21
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