Alternative titles; symbols
HGNC Approved Gene Symbol: PGR
Cytogenetic location: 11q22.1 Genomic coordinates (GRCh38): 11:101,029,624-101,129,813 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q22.1 | ?Progesterone resistance | 264080 | Autosomal recessive | 2 |
Progesterone plays a central role in the reproductive events associated with the establishment and maintenance of pregnancy. Progesterone receptor, a member of the steroid receptor superfamily, mediates the physiologic effects of progesterone. The PGR gene uses separate promoters and translational start sites to produce 2 isoforms, PRA and PRB, which are identical except for an additional 165 amino acids present only in the N terminus of PRB. Although PRA and PRB share several structural domains, they are distinct transcription factors that mediate their own response genes and physiologic effects with little overlap.
Misrahi et al. (1987) deduced the complete amino acid sequence of the human progesterone receptor from cloned cDNA.
Altered expression of several estrogen receptor (ER or ESR; 133430) variant mRNAs has been implicated in hormone-independent breast carcinoma. Several exon-deleted or truncated ER variant mRNAs have been observed in both normal and neoplastic tissues. Leygue et al. (1996) sought to determine if similar exon-deleted PR variant mRNAs could also be observed in human breast tissues. Using PCR amplification and sequence analysis to characterize the PR isoforms PRA, PRB, and PRC, previously identified by Horwitz and Alexander (1983) and Wei and Miner (1994), Leygue et al. (1996) identified the following PR mRNA variants in breast tissues: deletion of exon 4, deletion of exon 6, double deletion of exons 3 and 6, and double deletion of exons 5 and 6. They noted the existence of other variants as well. Leygue et al. (1996) stated that the functional significance of these variants is unknown, and hypothesized that, by analogy to the ER and other members of the steroid receptor superfamily, the diversity in PR-related transcripts could partly result from differential splicing.
Primary transcripts of the human ESR and PGR genes undergo a number of alternative splicing events that result in a range of variant mRNA isoforms in receptor-positive tissues. Despite in vitro demonstrations of a possible role for some of these isoforms in hormonal sensitivity, the clinical significance of this process is uncertain. By RT-PCR and Southern blot analysis, Balleine et al. (1999) documented the coexpression of variant ESR and PGR transcripts in a series of receptor-positive breast tumors. In 35 ESR-positive tumors, a common profile of variant ESR transcripts was present, with all tumors containing the exon 2-deleted and exon 7-deleted ESR variants, 94% containing the exon 4-deleted ESR variant, and 83% containing the exon 5-deleted ESR variant. In 25 of these cases, which were also PGR positive, the most highly expressed PGR variants, the exon 4-deleted PGR, exon 6-deleted PGR, and delta-4/2PGR, a transcript from which a 126-bp portion of PGR exon 4 was deleted, were detected in more than 90% of the cases. The alternatively spliced ESR isoforms were expressed at higher relative levels than the PGR isoforms, which had mean levels of expression less than 10% that of wildtype PGR. The most abundant isoform was the exon 7-deleted ESR, which was present at levels ranging from 29 to 83% of the wildtype. Balleine et al. (1999) concluded that the common profile of alternatively spliced ESR and PGR transcripts seen in breast tumors precludes its use as a discriminator of hormone responsiveness or other clinical end points. Furthermore, the low level of expression of the majority of variant isoforms called into question their potential for impacting significantly on receptor function.
Yeates et al. (1998) studied a smaller PR protein of molecular mass 78 kD, which they called PR78kDa. There was no evidence that PR78kDa was derived from proteolytic activity of either PRB or PRA. While exon-deleted PR transcripts were detected (which could, if translated, give rise to a PR protein similar in size to PR78kDa), neither the abundance of such transcripts nor their relationship to levels of expressed PR78kDa protein supported a role for exon deletion in formation of this truncated PR protein. PR78kDa was not recognized by an antibody specific for PRB, indicating that, like PRA, it lacks the N-terminal portion of PR. PR78kDa was able to bind the progestin ligand, indicating that it may have transcriptional activity. The authors concluded that the truncated PR protein, found in breast cancers, is ligand binding and seems to be derived from PRA, indicating that it may have a role in progesterone signaling.
Gong et al. (1997) generated 2 mutations of the alpha helix in the C-terminal portion of the ligand-binding domain of the PRB isoform. These were a point mutation and a short deletion. Both were expressed at levels comparable to that of the wildtype receptor in transfected cells. The point mutation showed hormone- and DNA-binding affinities similar to those of wildtype PRB, whereas the deletion mutation was defective in hormone and DNA binding. The point mutation inhibited transactivation by cotransfected wildtype PRB in a hormone-dependent fashion. The point mutation was less active when introduced into an N-terminal truncated form of PR, where it gave rise to proteins that formed homodimers with poor affinity for DNA, but were able to form heterodimers with PRB. Gong et al. (1997) concluded that the dominant-negative phenotype of the point mutation results from its competition with wildtype receptors for binding to DNA.
To study the function of progesterone receptor isoforms PRA and PRB in isolation, Miller et al. (1997) developed 2 stable breast cancer cell lines that expressed either PRA (YA cells) or PRB (YB cells). YA or YB cells were left untreated or were treated with the synthetic progestin R5020, and the mRNAs in each cell line under the 2 conditions were analyzed by differential display. Two message species were found to be regulated by only PRB. One of these is regulated in a ligand-independent manner. A third set of messages, encoding flavin-containing monooxygenase 5 (FMO5; 603957), was induced by R5020 only in YB cells. PRA appeared to be inhibitory. Since FMO5 is involved in the metabolic activation of drugs including tamoxifen, the authors concluded that progesterone may enhance the carcinogenicity of tamoxifen in target tissues that overexpress PRB by upregulating FMO5.
The human progesterone receptor exists as 2 functionally distinct isoforms, PRA and PRB. PRB functions as a transcriptional activator in most cell and promoter contexts, while PRA is transcriptionally inactive and functions as a strong ligand-dependent transdominant repressor of steroid hormone receptor transcriptional activity. The first 140 amino acids of PRA contain an inhibitory domain (ID); deletion of the N-terminal 140 amino acids from PRA results in a receptor mutant that is functionally indistinguishable from PRB (Giangrande et al., 1997). Using phage display technology, Giangrande et al. (2000) identified PRA-selective peptides that differentially modulate PRA and PRB transcriptional activity. Furthermore, using a combination of in vitro and in vivo methods, they demonstrated that the 2 receptors exhibit different cofactor interactions. Specifically, PRA has a higher affinity for the corepressor SMRT (600848) than does PRB, and this interaction is facilitated by the ID. Inhibition of SMRT activity by either a dominant-negative mutant (C'SMRT) or histone deacetylase inhibitors reversed PRA-mediated transrepression but did not convert PRA to a transcriptional activator. Together, these data indicated that the ability of PRA to transrepress steroid hormone receptor transcriptional activity and its inability to activate progesterone-responsive promoters occur by distinct mechanisms. Unlike PRB, PRA was unable to efficiently recruit the transcriptional coactivators GRIP1 (601993) and SRC1 (602691) upon agonist binding. Thus, although both receptors contain sequences within their ligand-binding domains known to be required for coactivator binding, the ability of PR to interact with cofactors in a productive manner is regulated by sequences contained within the amino terminus of the receptors. The authors proposed that PRA is transcriptionally inactive due to its inability to efficiently recruit coactivators. Furthermore, they concluded that PRA interacts efficiently with the corepressor SMRT and that this activity permits it to function as a transdominant repressor.
Boonyaratanakornkit et al. (2001) identified a specific polyproline motif in the N-terminal domain of PR that mediates direct progestin-dependent interaction of PR with SH3 domains of various cytoplasmic signaling molecules, including SRC tyrosine kinases. Through this interaction, PR is a potent activator of SRC kinases working by an SH3 domain displacement mechanism. By mutagenesis, the authors showed that rapid progestin-induced activation of SRC and downstream MAP kinase in mammalian cells is dependent on PR-SH3 domain interaction but not on the transcriptional activity of PR. The authors found that this interaction may influence the progestin-induced growth arrest of breast epithelial cells and induction of Xenopus oocyte maturation.
Attia et al. (2000) determined the levels of PR isoforms PRA and PRB in eutopic endometrial and extraovarian endometriotic tissues. It was proposed that progesterone action on target genes is mediated primarily by homodimers of PRB, whereas the truncated variant PRA acts as a repressor of PRB function. PRB was present in 17 of 18 eutopic endometrial samples, and its level increased in the preovulatory phase, as expected, whereas PRA was detected in all 18 samples with a similar, but less prominent, cyclic variation in its levels. In endometriotic samples, however, no detectable PRB could be demonstrated, whereas PRA was detected in all samples, albeit in much lower levels and without any cyclic variation in contrast with the eutopic endometrium. Using RNase protection assay, they also demonstrated indirectly that only PRA transcripts were present in 8 endometriotic tissue samples, whereas both PRA and PRB transcripts were readily detectable in all eutopic endometrial samples. The authors concluded that progesterone resistance (264080) in endometriotic tissue from laboratory and clinical observations may be accounted for by the presence of the inhibitory PR isoform PRA and the absence of the stimulatory isoform PRB.
Using in situ hybridization, Brisken et al. (2000) demonstrated that the progesterone receptor and Wnt4 (603490) mRNAs colocalize to the luminal compartment of the ductal epithelium, consistent with a model in which progesterone signaling induces Wnt4 expression. Using transplantation of mammary epithelia and hormone replacement experiments in mice, they concluded that Wnt signaling is essential in mediating progesterone function during mammary gland morphogenesis.
Auboeuf et al. (2002) examined the impact of transcription mediated by steroid receptors, including progesterone and estrogen receptors, on RNA processing using reporter genes subject to alternative splicing driven by steroid-sensitive promoters. Steroid hormones affected the processing of pre-mRNA synthesized from steroid-sensitive promoters, but not from steroid unresponsive promoters, in a steroid receptor-dependent and receptor-selective manner. Several nuclear receptor coregulators showed differential splicing effects, suggesting that steroid hormone receptors may simultaneously control gene transcription activity and exon content of the product mRNA by recruiting coregulators involved in both processes.
cAMP is required for the progesterone-induced differentiation of human endometrial stromal cells (HESCs) into decidual cells. Jones et al. (2006) showed that cAMP signaling attenuated ligand-dependent sumoylation of PGR in HESCs. They found that PIAS1 (603566) interacted with PGR and served as its E3 SUMO ligase upon receptor activation. Silencing PIAS1 not only enhanced PGR-dependent transcription, but also induced expression of prolactin (PRL; 176760), a decidual marker gene, in progestin-treated HESCs without the need of simultaneous activation of the cAMP pathway. Jones et al. (2006) concluded that dynamic changes in the SUMO pathway mediated by cAMP signaling determine the endometrial response to progesterone.
Mohammed et al. (2015) showed that PR is not merely an estrogen receptor-alpha (ER-alpha; 133430)-induced gene target, but is also an ER-alpha-associated protein that modulates its behavior. In the presence of agonist ligands, PR associates with ER-alpha to direct ER-alpha chromatin binding events within breast cancer cells, resulting in a unique gene expression program that is associated with good clinical outcome. Progesterone inhibited estrogen-mediated growth of ER-alpha(+) cell line xenografts and primary ER-alpha(+) breast tumor explants, and had increased antiproliferative effects when coupled with an ER-alpha antagonist. Copy number loss of the PGR gene is a common feature in ER-alpha(+) breast cancers, explaining lower PR levels in a subset of cases. Mohammed et al. (2015) concluded that their findings indicated that PR functions as a molecular rheostat to control ER-alpha chromatin binding and transcriptional activity.
Law et al. (1987) mapped the progesterone receptor gene to 11q13 by means of a human PGR cDNA probe used in genomic DNA blotting of hamster-human cell hybrids and in situ hybridization. 11q13 is also the site of the human homolog of the mouse mammary tumor virus integration site int2 (164950), which surrounds a protooncogene thought to be involved in the development of murine mammary cancers. In an erratum, the authors of Law et al. (1987) stated that in situ hybridization analysis located PGR to 11q21-q23 and that this localization had been independently confirmed by using human/Chinese hamster cell hybrids containing various deletions and translocations of human chromosome 11. Because of the distance that this indicates between PGR and INT2, they concluded that a functional connection between the 2 genes is less likely than was earlier considered to be the case.
Rousseau-Merck et al. (1987) mapped the PGR gene to chromosome 11 by direct molecular hybridization to sorted chromosomes (the flow blot method). They assigned the gene to 11p11-qter. Using 2 cDNA probes corresponding to the 5-prime and 3-prime parts of the coding sequence, Rousseau-Merck et al. (1987) localized the PGR gene to 11q22-q23 by in situ hybridization. Mattei et al. (1987, 1988) localized the PGR gene to 11q22 by in situ hybridization. Because of the conflicting localization to 11q13, they studied the chromosomes of a subject with a balanced translocation t(9;11)(p22;q21); PGR mapped distal to 11q21. By analysis of mouse/Chinese hamster hybrid cell DNAs, Naylor et al. (1989) demonstrated that the Pgr locus is on mouse chromosome 9.
Excessive estrogen stimulation unopposed by progesterone strongly predisposes to endometrial cancer. Because the antiproliferative effect of progesterone requires PGR, De Vivo et al. (2002) reasoned that variants in the PGR gene may predispose to endometrial cancer. They identified 6 variable sites, including 4 polymorphisms in the PGR gene, and 5 common haplotypes. One promoter region polymorphism, +331G-A, created a unique transcription start site. Biochemical assays showed that the +331G-A polymorphism increased transcription of the PGR gene, favoring production of PRB in an endometrial cancer cell line. Using a case-control study nested within the Nurses' Health Study cohort, De Vivo et al. (2002) observed a statistically significant association between the +331G-A polymorphism and the risk of endometrial cancer, which was even greater in overweight women carriers. After including a second population of controls, these associations remained intact. The findings suggested that the +331G-A polymorphism may contribute to endometrial cancer risk by increasing expression of the PRB isoform.
Ovulation is a precisely timed process by which a mature oocyte is released from an ovarian follicle. This process is initiated by the pituitary surge of luteinizing hormone (LH; 152780), is temporarily associated with the transcriptional regulation of numerous genes, and is presumed to involve the synthesis and/or activation of specific proteases that degrade the follicle wall. The progesterone receptor, a nuclear receptor transcription factor, is induced in granulosa cells of preovulatory follicles in response to the LH surge and is essential for ovulation, because mice lacking PGR fail to ovulate and are infertile. Using these mice as a model in which to elucidate PGR-regulated genes in the ovulation process, Robker et al. (2000) showed that the matrix metalloproteinases MMP2 (120360) and MMP9 (120361) are not targets of PGR during ovulation. In contrast, 2 other proteases, ADAMTS1 and cathepsin L (CTSL; 116880), are transcriptional targets of PGR action. ADAMTS1 was induced after LH stimulation in granulosa cells of preovulatory follicles and depended on PGR. Cathepsin L was induced in granulosa cells of growing follicles by follicle-stimulating hormone (FSHB; 136530), but the highest levels of cathepsin L mRNA occurred in preovulatory follicles in response to LH in a PGR-dependent manner. The identification of 2 regulated proteases in the ovary, together with their abnormal expression in anovulatory PGR knockout mice, suggested that each plays a critical role in follicular rupture and represents a major advance in the understanding of the proteolytic events that control ovulation.
Mulac-Jericevic et al. (2000) generated mice with selective ablation of PRA. All animals appeared normal except that PRA -/- females were infertile, a phenotype that was similar to that previously observed in progesterone receptor knockout mice in which both PR isoforms were ablated (Lydon et al., 1995). In response to superovulation stimuli, PRA -/- mice produced reduced numbers of oocytes, whereas PR -/- mice produced no oocytes. Crosses between superovulated PRA -/- females and wildtype males also failed to result in successful pregnancies despite the release of a small number of oocytes from PRA -/- females. Uteri of these females failed to show decidualization of stromal cells in response to traumal stimulation, indicating that infertility was also associated with defective uterine implantation. Ablation of PRA resulted in complete loss of regulation of calcitonin (114130), whereas the regulation of histidine decarboxylase (142704) was retained. Progesterone-induced expression of amphiregulin (104640) was also lost in PRA -/- mice, suggesting that defective implantation in PRA -/- uteri is associated with loss of progesterone-regulated expression of a subset of genes associated with receptivity. PRA -/- mice had normal proliferation and differentiation of mammary epithelium in response to progesterone, suggesting that PRB alone is sufficient to induce this response. PRA -/- mice also had normal thymic involution, a process shown to be progesterone receptor-dependent (Tibbetts et al., 1999).
Gestational diabetes (125851) coincides with elevated circulating progesterone levels. Picard et al. (2002) showed that progesterone accelerates the progression of diabetes in female db/db mice. In contrast, RU486, an antagonist of the progesterone receptor, reduces blood glucose levels in both female wildtype and db/db mice. Furthermore, female, but not male, PR -/- mice had lower fasting glycemia than PR +/+ mice and showed higher insulin levels on glucose injection. Pancreatic islets from female PR -/- mice were larger and secreted more insulin consequent to an increase in beta-cell mass due to an increase in beta-cell proliferation. These findings demonstrated an important role of progesterone signaling in insulin release and pancreatic function and suggested that it affects susceptibility to diabetes.
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