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RU486 exerts antiestrogenic activities through a novel progesterone receptor A form-mediated mechanism.

Publication ,  Journal Article
McDonnell, DP; Goldman, ME
Published in: J Biol Chem
April 22, 1994

The human progesterone receptor (hPR) exists in two distinct forms in most cells, hPR-A and hPR-B. Both receptor isoforms exhibit distinct biological functions and demonstrate a cell- and promoter-specific ability to regulate gene transcription. Interestingly, in cell contexts where PR-A is transcriptionally inactive, it acts as a progesterone-dependent inhibitor of estrogen receptor function. Coexpression of the human estrogen receptor with the A form (but not the B form) of the human progesterone receptor resulted in a ligand-dependent inhibition of estrogen receptor-mediated gene transcription. The antiprogestins RU486 (MIfepristone) and ZK98299 (Onapristone) and related antiprogestins were all effective "noncompetitive" inhibitors of the estrogen receptor in this assay as none of these compounds interacted directly with the estrogen receptor. This observation may explain in part the observed tissue-specific antiestrogenic effects of RU486 and further indicates that the antiestrogenic activities of antiprogestins may be intrinsic to their biological function. This important new information defines novel activities of progesterone receptor ligands and may alter the way in which we define progesterone receptor modulators for future clinical applications. In addition, these data reveal that the A form of the progesterone receptor plays a key role in modulating estrogen receptor function in cells where both receptors are expressed.

Duke Scholars

Published In

J Biol Chem

ISSN

0021-9258

Publication Date

April 22, 1994

Volume

269

Issue

16

Start / End Page

11945 / 11949

Location

United States

Related Subject Headings

  • Transfection
  • Receptors, Progesterone
  • Promoter Regions, Genetic
  • Progesterone
  • Polyunsaturated Alkamides
  • Plasmids
  • Oligodeoxyribonucleotides
  • Molecular Sequence Data
  • Mifepristone
  • Kidney
 

Citation

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McDonnell, D. P., & Goldman, M. E. (1994). RU486 exerts antiestrogenic activities through a novel progesterone receptor A form-mediated mechanism. J Biol Chem, 269(16), 11945–11949.
McDonnell, D. P., and M. E. Goldman. “RU486 exerts antiestrogenic activities through a novel progesterone receptor A form-mediated mechanism.J Biol Chem 269, no. 16 (April 22, 1994): 11945–49.
McDonnell DP, Goldman ME. RU486 exerts antiestrogenic activities through a novel progesterone receptor A form-mediated mechanism. J Biol Chem. 1994 Apr 22;269(16):11945–9.
McDonnell, D. P., and M. E. Goldman. “RU486 exerts antiestrogenic activities through a novel progesterone receptor A form-mediated mechanism.J Biol Chem, vol. 269, no. 16, Apr. 1994, pp. 11945–49.
McDonnell DP, Goldman ME. RU486 exerts antiestrogenic activities through a novel progesterone receptor A form-mediated mechanism. J Biol Chem. 1994 Apr 22;269(16):11945–11949.

Published In

J Biol Chem

ISSN

0021-9258

Publication Date

April 22, 1994

Volume

269

Issue

16

Start / End Page

11945 / 11949

Location

United States

Related Subject Headings

  • Transfection
  • Receptors, Progesterone
  • Promoter Regions, Genetic
  • Progesterone
  • Polyunsaturated Alkamides
  • Plasmids
  • Oligodeoxyribonucleotides
  • Molecular Sequence Data
  • Mifepristone
  • Kidney