PMID- 10598582
OWN - NLM
STAT- MEDLINE
DCOM- 20000110
LR  - 20131121
IS  - 0888-8809 (Print)
IS  - 0888-8809 (Linking)
VI  - 13
IP  - 12
DP  - 1999 Dec
TI  - A C619Y mutation in the human androgen receptor causes inactivation and
      mislocalization of the receptor with concomitant sequestration of SRC-1 (steroid 
      receptor coactivator 1)
PG  - 2065-75
AB  - Androgen ablation therapy is a primary treatment for advanced prostate cancer,
      but tumors become refractive to therapy. Consequently, the role of the androgen
      receptors (ARs) and of mutations in the AR in prostate cancer has been a subject 
      of much concern. In the course of analyzing tumors for mutations, we identified a
      somatic mutation that substitutes tyrosine for a cysteine at amino acid 619
      (C619Y), which is near the cysteines that coordinate zinc in the DNA binding
      domain in the AR. The mutation was re-created in a wild-type expression vector
      and functional analyses carried out using transfection assays with
      androgen-responsive reporters. The mutant is transcriptionally inactive and
      unable to bind DNA. In response to ligand treatment, AR619Y localizes abnormally 
      in numerous, well circumscribed predominantly nuclear aggregates in the nucleus
      and cytoplasm. Interestingly, these aggregates also contain the bulk of the
      coexpressed steroid receptor coactivator SRC-1, suggesting, in analogy to AR in
      spinal bulbar muscular atrophy, that this mutant may alter cellular physiology
      through sequestration of critical proteins. Although many inactivating mutations 
      have been identified in androgen insensitivity syndrome patients, to our
      knowledge, this is the first characterization of an inactivating mutation
      identified in human prostate cancer.
FAU - Nazareth, L V
AU  - Nazareth LV
AD  - Department of Molecular and Cellular Biology, Baylor College of Medicine,
      Houston, Texas 77030, USA.
FAU - Stenoien, D L
AU  - Stenoien DL
FAU - Bingman, W E 3rd
AU  - Bingman WE 3rd
FAU - James, A J
AU  - James AJ
FAU - Wu, C
AU  - Wu C
FAU - Zhang, Y
AU  - Zhang Y
FAU - Edwards, D P
AU  - Edwards DP
FAU - Mancini, M
AU  - Mancini M
FAU - Marcelli, M
AU  - Marcelli M
FAU - Lamb, D J
AU  - Lamb DJ
FAU - Weigel, N L
AU  - Weigel NL
LA  - eng
GR  - CA-68615/CA/NCI NIH HHS/United States
GR  - HD-07165/HD/NICHD NIH HHS/United States
GR  - T32 DK-07696/DK/NIDDK NIH HHS/United States
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Endocrinol
JT  - Molecular endocrinology (Baltimore, Md.)
JID - 8801431
RN  - 0 (Receptors, Androgen)
RN  - 0 (Transcription Factors)
RN  - 42HK56048U (Tyrosine)
RN  - 9007-49-2 (DNA)
RN  - EC 2.3.1.48 (Histone Acetyltransferases)
RN  - EC 2.3.1.48 (NCOA1 protein, human)
RN  - EC 2.3.1.48 (Nuclear Receptor Coactivator 1)
RN  - K848JZ4886 (Cysteine)
SB  - IM
EIN - Mol Endocrinol 2000 Apr;14(4):544
MH  - Cell Nucleus/metabolism
MH  - Chromosome Mapping
MH  - Cysteine
MH  - Cytoplasm/metabolism
MH  - DNA/metabolism
MH  - HeLa Cells/metabolism/ultrastructure
MH  - Histone Acetyltransferases
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - *Mutation
MH  - Nuclear Receptor Coactivator 1
MH  - Prostatic Neoplasms/*genetics
MH  - Receptors, Androgen/analysis/*genetics/metabolism
MH  - Response Elements
MH  - Transcription Factors/*metabolism
MH  - Transfection
MH  - Tyrosine
MH  - X Chromosome
EDAT- 1999/12/22 09:00
MHDA- 2001/03/28 10:01
CRDT- 1999/12/22 09:00
PHST- 1999/12/22 09:00 [pubmed]
PHST- 2001/03/28 10:01 [medline]
PHST- 1999/12/22 09:00 [entrez]
AID - 10.1210/mend.13.12.0382 [doi]
PST - ppublish
SO  - Mol Endocrinol. 1999 Dec;13(12):2065-75. doi: 10.1210/mend.13.12.0382.