PMID- 15027889
OWN - NLM
STAT- MEDLINE
DCOM- 20041012
LR  - 20191210
IS  - 1351-0088 (Print)
IS  - 1351-0088 (Linking)
VI  - 11
IP  - 1
DP  - 2004 Mar
TI  - Mechanisms of androgen receptor signalling via steroid receptor coactivator-1 in 
      prostate.
PG  - 117-30
AB  - The androgen receptor (AR) is a member of the nuclear receptor superfamily. These 
      ligand-activated transcription factors usually contain two activation functions, 
      a ligand-independent activation function 1(AF1) in the divergent N-terminal 
      domain and a ligand-dependent AF2 in the more conserved C-terminal ligand-binding 
      domain. To promote transcription from target promoters, DNA-bound nuclear 
      receptors recruit coactivator proteins that promote transcription by modifying 
      histones within nucleosomes, resulting in altered topology of chromatin to allow 
      access of the basal transcriptional machinery, or stabilising the pre-initiation 
      complex. It is well known that most coactivators interact with AF2 of many 
      nuclear receptors via conserved, helical LxxLL motifs (where L is leucine and x 
      is any amino acid). The AF2 of the AR is very weak, but we were able to 
      demonstrate that its intrinsic ligand-dependent activity is potentiated by 
      steroid receptor coactivator-1 (SRC1) and that this region interacts with 
      coactivators via LxxLL motifs. However, a mutant SRC1 coactivator with no 
      functional LxxLL motifs was still able to potentiate AR activity. We found that 
      SRC1 can also be recruited to (and increase activity of) AF1 of the AR via a 
      conserved, glutamine-rich region. Point mutations within this region abolish SRC1 
      interaction with AF1 and also abolish or severely impair its ability to 
      potentiate AR activity on all promoters tested. Thus the AR interacts with SRC1 
      via two different regions and the AF1 interaction is functionally the more 
      important, although the contribution of the two interactions varies in a 
      promoter-dependent fashion. SRC1 then potentiates receptor activity via 
      recruitment of CBP/p300, a histone acetyltranferase. This is important in the 
      context of prostate cancer as SRC1 and other coactivators including CBP are 
      coexpressed with AR in the luminal epithelial cells of the prostate, where over 
      90% of prostate tumours arise. There is a need for effective second-line prostate 
      cancer therapy aimed at blocking the AR pathway when anti-androgen therapy has 
      failed. Since there is growing evidence that nuclear receptor cofactors may be 
      implicated in the progression of hormone-dependent tumours to hormone-independent 
      states, novel targets could include the interaction of AR with coactivator 
      proteins. We suggest that the N-terminal interaction would be a more specific and 
      effective target in the case of prostate cancer than the LxxLL/AF2 interaction.
FAU - Powell, S M
AU  - Powell SM
AD  - Prostate Cancer Research Group, Department of Cancer Medicine, Imperial College 
      London, Hammersmith Hospital, London W12 0NN, UK.
FAU - Christiaens, V
AU  - Christiaens V
FAU - Voulgaraki, D
AU  - Voulgaraki D
FAU - Waxman, J
AU  - Waxman J
FAU - Claessens, F
AU  - Claessens F
FAU - Bevan, C L
AU  - Bevan CL
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Endocr Relat Cancer
JT  - Endocrine-related cancer
JID - 9436481
RN  - 0 (Receptors, Androgen)
RN  - 0 (Transcription Factors)
RN  - EC 2.1.1.- (Histone Methyltransferases)
RN  - EC 2.1.1.- (Protein Methyltransferases)
RN  - EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
RN  - EC 2.3.1.- (Acetyltransferases)
RN  - EC 2.3.1.48 (Histone Acetyltransferases)
RN  - EC 2.3.1.48 (Nuclear Receptor Coactivator 1)
RN  - GMW67QNF9C (Leucine)
SB  - IM
MH  - Acetyltransferases/metabolism
MH  - Amino Acid Motifs
MH  - Animals
MH  - COS Cells
MH  - Chlorocebus aethiops
MH  - Gene Expression
MH  - Histone Acetyltransferases
MH  - Histone Methyltransferases
MH  - Histone-Lysine N-Methyltransferase/metabolism
MH  - Immunochemistry
MH  - Leucine/chemistry/metabolism
MH  - Male
MH  - Nuclear Receptor Coactivator 1
MH  - Prostate/*metabolism
MH  - Protein Interaction Mapping
MH  - Protein Methyltransferases
MH  - Protein Structure, Tertiary
MH  - Receptors, Androgen/*metabolism
MH  - Sequence Alignment
MH  - *Signal Transduction
MH  - Transcription Factors/*metabolism
MH  - Two-Hybrid System Techniques
MH  - Yeasts/metabolism
EDAT- 2004/03/19 05:00
MHDA- 2004/10/13 09:00
CRDT- 2004/03/19 05:00
PHST- 2004/03/19 05:00 [pubmed]
PHST- 2004/10/13 09:00 [medline]
PHST- 2004/03/19 05:00 [entrez]
AID - 10.1677/erc.0.0110117 [doi]
PST - ppublish
SO  - Endocr Relat Cancer. 2004 Mar;11(1):117-30. doi: 10.1677/erc.0.0110117.