PMID- 9806358
OWN - NLM
STAT- MEDLINE
DCOM- 19990105
LR  - 20190813
IS  - 0303-7207 (Print)
IS  - 0303-7207 (Linking)
VI  - 143
IP  - 1-2
DP  - 1998 Aug 25
TI  - Studies of dehydroepiandrosterone (DHEA) with the human estrogen receptor in 
      yeast.
PG  - 133-42
AB  - Dehydroepiandrosterone (DHEA) is a C19 adrenal steroid synthesized in the human 
      adrenal cortex and serving as a biosynthetic precursor to testosterone and 
      17beta-estradiol. Despite the fact that it is one of the most abundant steroid 
      hormones in circulation, the physiological role of DHEA in humans remains 
      unclear. The action of DHEA itself, such as its interactions with receptors and 
      nuclear transcription factors, is not well understood, and a specific DHEA 
      receptor has yet to be identified. Although the activity of DHEA can be due to 
      its metabolism into androgens and estrogens, DHEA has been shown to interact with 
      the androgen receptor and the estrogen receptor (ER) in vitro. We demonstrate in 
      this study that DHEA (3beta-Hydroxy-5alpha-androstan-17-one) inhibits 
      17beta-estradiol (E2) binding to its receptor in vivo in yeast. DHEA stimulates 
      human ER dimerization in yeast, as determined by ER fusion protein interactions, 
      GAL4 reconstitution and subsequent measurement of increased beta-galactosidase 
      activity. DHEA causes an increase in estrogen response element-dependent 
      beta-galactosidase activity, demonstrating that the ER dimer induced by DHEA is 
      transcriptionally active, but at a concentration of DHEA about 1000 times greater 
      than E2. Inclusion of the nuclear receptor co-activator RIP140 in the yeast 
      enhances ER transactivation by DHEA or E2 in a ligand-dependent manner; moreover, 
      only in the presence of RIP140 is DHEA able to stimulate beta-galactosidase 
      activity to levels similar to those achieved by E2. Ligand-receptor interaction 
      for other C19-steroids was also examined. While 5-androstene-3beta, 17beta-diol 
      (ADIOL) displayed estrogenic activity in this system, 4-androstene-17-dione 
      (androstenedione) and 4-androstene-17beta-ol,3-one (testosterone) did not. We 
      have investigated whether DHEA can interact with the human ER in vivo. Our 
      findings demonstrate a mechanism by which DHEA interacts directly with estrogen 
      signaling systems; however, because DHEA is several orders of magnitude less 
      potent than E2 in this system, we conclude that it essentially is not an estrogen 
      agonist.
FAU - Nephew, K P
AU  - Nephew KP
AD  - Medical Sciences Program, Indiana University School of Medicine, Bloomington 
      47405-4401, USA. knephew@indiana.edu
FAU - Sheeler, C Q
AU  - Sheeler CQ
FAU - Dudley, M D
AU  - Dudley MD
FAU - Gordon, S
AU  - Gordon S
FAU - Nayfield, S G
AU  - Nayfield SG
FAU - Khan, S A
AU  - Khan SA
LA  - eng
GR  - CA72309/CA/NCI NIH HHS/United States
GR  - CA74748/CA/NCI 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  - Ireland
TA  - Mol Cell Endocrinol
JT  - Molecular and cellular endocrinology
JID - 7500844
RN  - 0 (Estrogens)
RN  - 0 (Receptors, Estrogen)
RN  - 0 (Recombinant Proteins)
RN  - 459AG36T1B (Dehydroepiandrosterone)
SB  - IM
MH  - Dehydroepiandrosterone/*metabolism/pharmacology
MH  - Estrogens/metabolism
MH  - Humans
MH  - Receptors, Estrogen/*metabolism
MH  - Recombinant Proteins/metabolism
MH  - Saccharomyces cerevisiae
MH  - Signal Transduction
MH  - Transfection
EDAT- 1998/11/07 00:00
MHDA- 1998/11/07 00:01
CRDT- 1998/11/07 00:00
PHST- 1998/11/07 00:00 [pubmed]
PHST- 1998/11/07 00:01 [medline]
PHST- 1998/11/07 00:00 [entrez]
AID - S0303-7207(98)00128-2 [pii]
AID - 10.1016/s0303-7207(98)00128-2 [doi]
PST - ppublish
SO  - Mol Cell Endocrinol. 1998 Aug 25;143(1-2):133-42. doi: 
      10.1016/s0303-7207(98)00128-2.