Disease relevance of Pgr

• Anthrax lethal factor represses glucocorticoid and progesterone receptor activity [1].
• PR-B overexpression by adenovirus infection induced p27 and suppressed cell growth [2].
• Thus, mouse mammary stem cells were negative for ERalpha, PR, and ErbB2 and appeared to share common properties with poor-prognosis basal breast cancer [3].
• We previously reported that transiently expressed progesterone receptor (PR) cannot activate mouse mammary tumor virus (MMTV) promoter when it adopts the form of ordered chromatin [4].
• In the C3H mouse mammary adenocarcinoma, estradiol cannot induce the progesterone receptor, and the tumor growth rate is not decreased by ovariectomy [5].

Psychiatry related information on Pgr

• These results suggest that androgens may interact with either AR or PR, and perhaps both receptors, in E2 + TP-induced mammary glands and the induced tumors to effect the reduction in latency period, enhance tumor size, and increase incidence to 100% [6].

High impact information on Pgr

• Here we describe a crude in vitro system in which transcription from the mouse mammary tumour virus (MMTV) promoter is increased up to 10-fold by native progesterone receptor from rabbit uterus [7].
• The transactivation activity of the progesterone receptor depends on binding of a functional ligand and so this assay should be useful for dissection of the mechanism of transcription activation by steroid hormones [7].
• The nuclear factor-I binding site immediately downstream of the HRE, however, does not appear to be essential to progesterone receptor-mediated in vitro stimulation of MMTV transcription [7].
• Progesterone receptor stimulates transcription of mouse mammary tumour virus in a cell-free system [7].
• Thus, PR-A and PR-B are functionally distinct mediators of progesterone action in vivo and should provide suitable targets for generation of tissue-selective progestins [8].

Chemical compound and disease context of Pgr

• Transcription studies in +/+ and -/- mouse embryonic fibroblast cells showed a near-complete loss of PR-A activity at mouse mammary tumor virus and synthetic progesterone response element promoters, although partial reductions of ER and PR-B were also observed [9].
• We have evaluated the progesterone receptor (PR) binding patterns in progestin-dependent and -independent murine mammary carcinomas; all variants regress completely after antiprogestin treatment [10].
• The purpose of this study was to evaluate the effect of the selective estrogen receptor modulators raloxifene and tamoxifen and of the pure antiestrogen fulvestrant on tumor growth and progesterone receptor (PR) expression in an experimental model of breast cancer [11].
• Medroxyprogesterone acetate (MPA)-induced mammary carcinomas express high levels of estrogen (ER) and progesterone receptors (PR) and when transplanted in syngeneic mice they show a progestin-dependent (PD) growth pattern [12].
• We show that, as a group, E2-regulated genes from our preclinical models were co-expressed with ERalpha in a panel of ERalpha+ breast tumor mRNA profiles, when corrections were made for patient age, as well as with progesterone receptor [13].

Biological context of Pgr

• The identification of two regulated proteases in the ovary, together with their abnormal expression in anovulatory PR knockout mice, suggests that each plays a critical role in follicular rupture and represents a major advance in our understanding of the proteolytic events that control ovulation [14].
• The PR-A and PR-B isoforms are both detected on Western blot, and the ratio of isoforms is the same in both genotypes [15].
• We conclude that SRC-2 is appropriated by PR in a subset of transcriptional cascades obligate for normal uterine and mammary morphogenesis and function [16].
• Progesterone receptor (PR), a ligand-activated transcription factor, is a key regulator of cellular proliferation and differentiation in reproductive tissues [17].
• Surprisingly, one of the earliest changes in gene expression in response to a differentiation signal observed is PR gene induction [18].

Anatomical context of Pgr

• In the BERKO uterus, E(2) induced PR in the stroma but did not down-regulate it in the epithelium [19].
• As expected, E(2) increased PR in the stroma and decreased it in the luminal epithelium of wild-type mice [19].
• Progesterone receptor mRNA was not detectable until the blastocyst stage [20].
• In the case of the mammary gland, whole-mount and histological analysis disclosed the absence of significant ductal side branching and alveologenesis in the hormone-treated PR(Cre/+) SRC-2(flox/flox) mammary gland, reinforcing an important role for SRC-2 in cellular proliferative changes that require PR [16].
• In the early pregnant uterus, Bteb1 expression in stromal cells temporally coincides with PR-A isoform-dependent decidual formation at the time of implantation [17].

Associations of Pgr with chemical compounds

• These results indicate that estrogen receptor alpha modulation of PR levels is not necessary for expression of the PR or genomic and physiologic responses to progesterone in the ERKO uterus [15].
• The estrogen receptor alpha knockout (ERKO) mouse uterus was observed to express PR mRNA that cannot be induced by estrogen [15].
• Recruitment was disrupted by cotreatment with progestin and PRL, suggesting a mutual interference between activated PR and Stat5a [21].
• Coordinate transcription of the ADAMTS-1 gene by luteinizing hormone and progesterone receptor [22].
• Forskolin plus phorbol myristate acetate also increased promoter activity and, when added to cells cotransfected with PRA, ADAMTS-1 promoter activity increased further [22].
• PRA was the predominant PR isoform expressed during sidebranching, and colocalization of PRA with 5-bromo-2'-deoxyuridine revealed that proliferation of PRA-positive and -negative cells was responsible for P-induced sidebranching [23].

Physical interactions of Pgr

• Furthermore, immunoprecipitation followed by Western blot analysis revealed that, under in vivo conditions, PRA physically interacted with GR in mouse lung [24].
• The murine progesterone receptor had complete identity for the DNA binding domain of human and rabbit progesterone receptors and 99% homology with the chicken progesterone receptor; for the steroid binding domain, it had 96% homology with human and rabbit progesterone receptors and 86% homology with chicken progesterone receptors [25].
• Progesterone receptor bound to the HRE facilitates binding of OTF-1 to the two octamer motifs [26].
• In silico analysis revealed progesterone receptor binding sites in the dermatopontin promoter region [27].

Regulatory relationships of Pgr

• Neurons in the hypothalamus of estrogen receptor alpha-knockout (ER alphaKO) mice have been shown to concentrate radiolabeled estrogen and estrogen treatment regulates the expression of progesterone receptor mRNA [28].
• In the virgin mammary gland when ductal development is active, the only PR protein isoform expressed was PRA [29].
• In male urethra, PR was co-expressed with ERbeta in the rhabdosphincter [30].
• Our studies identified Clca3 as a novel downregulated gene of PGR that is a direct target of E2 regulation [31].
• DNA mobility shift assay revealed that HRG was able to induce PR binding to a progesterone response element (PRE) in C4HD and T47D cells [32].

Other interactions of Pgr

• The spatial and temporal separation of PR isoform expression in mouse mammary gland provides a unique opportunity to determine the specific functions of PRA vs. PRB in vivo [29].
• These findings suggest that estrogen induces stromal PR via ERbeta in alphaERKO uterus [33].
• The whole-uterus level of PR and Hoxa10 mRNAs did not vary; however, the PR protein was induced in the stroma 24 h after oil infusion [34].
• Ribonuclease protection analyses showed that ovarian progesterone receptor and androgen receptor mRNA expression were similar in the two groups [35].
• As a result, betaERKO ovaries were unable to fully respond to an ovulatory bolus of gonadotropin, leading to a reduced rate of follicle rupture; insufficient induction of prostaglandin-synthase 2 and progesterone receptor; an aberrant increase in aromatase activity and plasma estradiol; and incomplete expansion of the cumulus-oocyte complex [36].

Analytical, diagnostic and therapeutic context of Pgr

• Progesterone Receptor Repression of Prolactin/Signal Transducer and Activator of Transcription 5-Mediated Transcription of the {beta}-Casein Gene in Mammary Epithelial Cells [21].
• The results of Northern and in situ hybridization demonstrated increased uterine levels of PR and LF messenger RNAs (mRNAs) by all of these xenobiotics, but quantitatively the responses were much lower than those induced by E2 or 4-OH-E2 [37].
• Interestingly, immunohistochemistry indicated that the induction of apoptosis by PR antagonists was predominant in the epithelium, whereas increase in PR protein expression was observed in stromal cells of both tissues [38].
• In organ cultures of alphaERKO uterus, both E(2) and diethylstilbestrol induced stromal PR, and ICI inhibited this induction [33].
• In previous studies, using high-density DNA microarray analysis, we identified a subset of genes whose expression is repressed by chronic P4-PGR activation in the uterus [31].

References