Progesterone receptor A

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]

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

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. ^ a b 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. ^ a b 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. ^ a b 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.


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