Progesterone receptor A

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The progesterone receptor A (PR-A) is one of three known isoforms of the progesterone receptor (PR), the main biological target of the endogenous progestogen sex hormone progesterone. [1] [2] The other isoforms of the PR include the PR-B and PR-C. [1] [2]

Contents

The AlphaFold predictive structure of the entire progesterone receptor with the region unique to isoform A highlighted in purple. Amino acids 1-164 are seen in grey as they are not included in isoform A. AlphaFold Identifier: AF-P060401-F Progesterone Receptor Isoform A.png
The AlphaFold predictive structure of the entire progesterone receptor with the region unique to isoform A highlighted in purple. Amino acids 1-164 are seen in grey as they are not included in isoform A. AlphaFold Identifier: AF-P060401-F

PR-A is 164 residues shorter than PR-B in humans [3] and anywhere from 128-165 residues shorter in other organisms. [4] Each isoform binds its natural ligand, progesterone, but also demonstrates the ability to bind a number of other agonists including norethindrone, a synthetic progestin. [5]

The crystallographic structure of the ligand-binding domain which is common to both isoforms A and B in its dimerized conformation (purple). Dimerization will only occur when a ligand is bound. The study which yielded this structure (Maduass et al. 2004) used agonists mometasone fuorate and norethindrone (grey) to induce dimerization. PBD Identifier: 1SQN Dimerized Progesterone Receptor Bound to Norethindrone 20250509.png
The crystallographic structure of the ligand-binding domain which is common to both isoforms A and B in its dimerized conformation (purple). Dimerization will only occur when a ligand is bound. The study which yielded this structure (Maduass et al. 2004) used agonists mometasone fuorate and norethindrone (grey) to induce dimerization. PBD Identifier: 1SQN

Expression and overexpression

PR-A and PR-B are generally expressed in equal ratios, [3] but PR-A is expressed in larger amounts in uterine stromal cells normally. [6] A spike in PR-A expression in the myometrium has been observed to initiate parturition in placental mammals. [7]

PR-A is the isoform most commonly observed to be overexpressed in human breast cancer. Currently PR is estimated by immunohistochemistry and earlier was quantified by standardized radio-ligand binding assays developed by New England Nuclear and Wittliff. [8] Patients with PR-A rich carcinomas, as opposed to patients with PR-B rich carcinomas, have faster recurrence rates. [9]

See also

References

  1. 1 2 Jacobsen BM, Horwitz KB (2012). "Progesterone receptors, their isoforms and progesterone regulated transcription". Mol. Cell. Endocrinol. 357 (1–2): 18–29. doi:10.1016/j.mce.2011.09.016. PMC   3272316 . PMID   21952082.
  2. 1 2 Scarpin KM, Graham JD, Mote PA, Clarke CL (2009). "Progesterone action in human tissues: regulation by progesterone receptor (PR) isoform expression, nuclear positioning and coregulator expression". Nucl Recept Signal. 7: e009. doi:10.1621/nrs.07009. PMC   2807635 . PMID   20087430.
  3. 1 2 Graham, J Dinny; Clarke, Christine L (October 2002). "Progesterone receptors - animal models and cell signaling in breast cancer: Expression and transcriptional activity of progesterone receptor A and progesterone receptor B in mammalian cells". Breast Cancer Research. 4 (5): 187–190. doi: 10.1186/bcr450 . ISSN   1465-542X. PMC   138742 . PMID   12223122.
  4. Conneely, O (November 2000). "Progesterone receptors in reproduction: functional impact of the A and B isoforms" . Steroids. 65 (10–11): 571–577. doi:10.1016/S0039-128X(00)00115-X. PMID   11108861.
  5. Madauss, Kevin P.; Deng, Su-Jun; Austin, Robert J. H.; Lambert, Millard H.; McLay, Iain; Pritchard, John; Short, Steven A.; Stewart, Eugene L.; Uings, Ian J.; Williams, Shawn P. (2004-06-01). "Progesterone Receptor Ligand Binding Pocket Flexibility: Crystal Structures of the Norethindrone and Mometasone Furoate Complexes" . Journal of Medicinal Chemistry. 47 (13): 3381–3387. doi:10.1021/jm030640n. ISSN   0022-2623. PMID   15189034.
  6. Bulun, Serdar E.; Cheng, You-Hong; Yin, Ping; Imir, Gonca; Utsunomiya, Hiroki; Attar, Erkut; Innes, Joy; Julie Kim, J. (March 2006). "Progesterone resistance in endometriosis: Link to failure to metabolize estradiol" . Molecular and Cellular Endocrinology. 248 (1–2): 94–103. doi:10.1016/j.mce.2005.11.041. PMID   16406281.
  7. Cope, Dominique; Monsivais, Diana (2022-04-27). "Progesterone Receptor Signaling in the Uterus Is Essential for Pregnancy Success". Cells. 11 (9): 1474. doi: 10.3390/cells11091474 . ISSN   2073-4409. PMC   9104461 . PMID   35563781.
  8. Fisher, B., Redmond, C., Brown, A., Wickerham, D. L., Wolmark, N., Allegra, J. C., Escher, G., Lippman, M., Savlov, E., Wittliff, J. L. and Fisher, E. R. et al. Influence of Tumor Estrogen and Progesterone Receptor Levels on the Response to Tamoxifen and Chemotherapy in Primary Breast Cancer. J. Clin. Oncol., 1:227-241, 1983. https://pubmed.ncbi.nlm.nih.gov/6366135/
  9. Timmermans-Sprang, Elpetra P. M.; Gracanin, Ana; Mol, Jan A. (2017-04-13). "Molecular Signaling of Progesterone, Growth Hormone, Wnt, and HER in Mammary Glands of Dogs, Rodents, and Humans: New Treatment Target Identification". Frontiers in Veterinary Science. 4: 53. doi: 10.3389/fvets.2017.00053 . ISSN   2297-1769. PMC   5389977 . PMID   28451590.