PMID- 10207098
OWN - NLM
STAT- MEDLINE
DCOM- 19990518
LR  - 20190508
IS  - 0270-7306 (Print)
IS  - 0270-7306 (Linking)
VI  - 19
IP  - 5
DP  - 1999 May
TI  - Role for Hsp90-associated cochaperone p23 in estrogen receptor signal
      transduction.
PG  - 3748-59
AB  - The mechanism of signal transduction by the estrogen receptor (ER) is complex and
      not fully understood. In addition to the ER, a number of accessory proteins are
      apparently required to efficiently transduce the steroid hormone signal. In the
      absence of estradiol, the ER, like other steroid receptors, is complexed with
      Hsp90 and other molecular chaperone components, including an immunophilin, and
      p23. This Hsp90-based chaperone complex is thought to repress the ER's
      transcriptional regulatory activities while maintaining the receptor in a
      conformation that is competent for high-affinity steroid binding. However, a role
      for p23 in ER signal transduction has not been demonstrated. Using a mutant ER
      (G400V) with decreased hormone binding capacity as a substrate in a dosage
      suppression screen in yeast cells (Saccharomyces cerevisiae), we identified the
      yeast homologue of the human p23 protein (yhp23) as a positive regulator of ER
      function. Overexpression of yhp23 in yeast cells increases ER transcriptional
      activation by increasing estradiol binding in vivo. Importantly, the magnitude of
      the effect of yhp23 on ER transcriptional activation is inversely proportional to
      the concentration of both ER and estradiol in the cell. Under conditions of high 
      ER expression, ER transcriptional activity is largely independent of yhp23,
      whereas at low levels of ER expression, ER transcriptional activation is
      primarily dependent on yhp23. The same relationship holds for estradiol levels.
      We further demonstrate that yhp23 colocalizes with the ER in vivo. Using a
      yhp23-green fluorescent protein fusion protein, we observed a redistribution of
      yhp23 from the cytoplasm to the nucleus upon coexpression with ER. This nuclear
      localization of yhp23 was reversed by the addition of estradiol, a finding
      consistent with yhp23's proposed role as part of the aporeceptor complex.
      Expression of human p23 in yeast partially complements the loss of yhp23 function
      with respect to ER signaling. Finally, ectopic expression of human p23 in MCF-7
      breast cancer cells increases both hormone-dependent and hormone-independent
      transcriptional activation by the ER. Together, these results strongly suggest
      that p23 plays an important role in ER signal transduction.
FAU - Knoblauch, R
AU  - Knoblauch R
AD  - Department of Microbiology and Kaplan Comprehensive Cancer Center, New York
      University School of Medicine, New York, New York 10016, USA.
FAU - Garabedian, M J
AU  - Garabedian MJ
LA  - eng
GR  - T32 GM007308/GM/NIGMS NIH HHS/United States
GR  - 2T32GM07308/GM/NIGMS NIH HHS/United States
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 Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (HSP90 Heat-Shock Proteins)
RN  - 0 (Luminescent Proteins)
RN  - 0 (Molecular Chaperones)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Receptors, Estrogen)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - 4TI98Z838E (Estradiol)
SB  - IM
MH  - Estradiol/pharmacology
MH  - Fluorescent Antibody Technique
MH  - Gene Expression Regulation, Fungal/genetics
MH  - Green Fluorescent Proteins
MH  - HSP90 Heat-Shock Proteins/*metabolism
MH  - Humans
MH  - Luminescent Proteins/genetics
MH  - Molecular Chaperones/*metabolism
MH  - Mutation/genetics
MH  - Nuclear Proteins/analysis
MH  - Receptors, Estrogen/genetics/*metabolism
MH  - Recombinant Fusion Proteins/metabolism
MH  - Saccharomyces cerevisiae/*genetics
MH  - *Signal Transduction
MH  - Suppression, Genetic
MH  - Transcriptional Activation/genetics
MH  - Tumor Cells, Cultured
PMC - PMC84199
EDAT- 1999/04/17 00:00
MHDA- 1999/04/17 00:01
CRDT- 1999/04/17 00:00
PHST- 1999/04/17 00:00 [pubmed]
PHST- 1999/04/17 00:01 [medline]
PHST- 1999/04/17 00:00 [entrez]
AID - 10.1128/mcb.19.5.3748 [doi]
PST - ppublish
SO  - Mol Cell Biol. 1999 May;19(5):3748-59. doi: 10.1128/mcb.19.5.3748.