een transcriptiefactor Androgens AR Δ Gene expression A A Androgens affect Embryologic development Bone and muscle Male puberty Behaviour ID: 734510
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Slide1
De
androgeenreceptor
is
een
transcriptiefactorSlide2
Androgens
AR
Δ
Gene expression
A
ASlide3
Androgens
affect:
-
Embryologic
development
- Bone and muscle
- Male puberty
- Behaviour
- Reproduction - Prostate & PrCa
- Osteoporosis and frailty
Androgens
Testosterone
Dihydrotestosterone Slide4
Androgens
AR
Δ
Gene expression
A
ASlide5
Gene
regulation by testosterone
Testosteron binds the androgen
receptor
The receptor
binds
DNA
The receptor
activates
gene
expression
TherapiesSlide6
DNA binding
Ligand
-binding
Gene activation
AF1
LBD AF2
AR:
DBD
The receptor
binds
testosteroneSlide7
Testosterone binds the receptorSlide8
Effect of testosterone binding
H1
H2
H3
H4
H5
6
H7
H8
H9
H10
H11
H12
S1
S2
W
no ligand
H9
H1
H2
H3
H4
H5
H7
H8
H10
H11
H12
W
6
T
+ ligand
LxxLLSlide9
Gene
regulation by testosterone
Testosteron activates the androgen receptor
The receptor
binds
DNA
The receptor activates gene expression
TherapiesSlide10
The
DNA-binding domain of the AR
AF1
LBD AF2
AR:
DBDSlide11
DNA binding
Ligand
-binding
How does testosterone affect gene expression?
Gene activation
AF1
LBD AF2
AR:
DBDSlide12
Gene
regulation by testosterone
Testosteron binds
the
androgen
receptor
The receptor
binds
DNA
The receptor
activates
gene
expression Slide13
Histon
code
recognition
erasing
TIF1
β
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
complexSlide14
-CRC
-TIF1b
Testosteron
effects
on
the
histon
code:
a
cartoon
AR
AR
AR
AR
-p160
RNA
polII
-TFIIFSlide15
DNA binding
Ligand
-binding
The DBD and LBD
communicate
Transactivation
Tau-1
LBD AF2
AR:
DBD
Tau-5
Cycling
partners
Cycling
histon
codeSlide16
Gene
regulation by testosterone
Testosteron binds the
androgen
receptor
The receptor
binds
DNA
The receptor
activates
gene
expression
Prostate cancerSlide17
6,6 x 10
9
bp: A,C,G or T 107 Single nucleotide polymorphisms Gene fusions
New markers in prostate cancerSlide18
Gene fusions in PCa
CTRL : Oncogenes
50% !Slide19
Two SNPs in the TM-enhancer
SNP2
SNP1
T
A
TM-ARE2
SNP1
SNP2
Chr 21: TMPRSS2 geneSlide20
Two SNPs in TM-ARE2
WT
SNP1
SNP2
TM-ARE2
SNP2
SNP1
T
A
Chr 21Slide21
Relevance of TM-ARE2 SNPs?Slide22
Mol Endo LabAR
stuctuur en functiePrCa resistentie tegen
AR antagonistenNieuwe AR antagonistenPrCa genomen en diagnostische merkersSNPs
Frailty: osteoporosis