Which of the following is a steroid hormone produced in the ovaries of the female?
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Orla M. Conneely 1Department of Molecular and Cellular Biology Baylor College of Medicine Houston, Texas 77030 *Address all correspondence and requests for reprints to: Orla M. Conneely, Ph.D., Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030. Search for other works by this author on:
Close Navbar Search Filter Microsite Search Term Search The steroid hormones estrogen (E) and progesterone (P) play a central role in the regulation of all aspects of female reproductive activity leading to the establishment and maintenance of pregnancy. Together, they act at the level of the hypothalamus, pituitary, ovary, and uterus to coordinate cyclic neuroendocrine gonadotropin production, ovulatory activity, and uterine development in preparation for implantation of fertilized embryos. Both hormones are also essential for postnatal mammary gland development regulating postpubertal mammary ductal morphogenesis in the case of E and pregnancy-associated lateral ductal branching and lobular alveolar differentiation in the case of P. The diverse physiological activities of E and P, however, are not restricted to the female reproductive system. Estrogen is essential for male fertility, and both hormones have been implicated in the cardiovascular, immune, and central nervous systems and in bone function. In particular, estrogen has been shown to play an important role in protection against osteoporosis in postmenopausal women (1), in the prevention of coronary heart disease (2) and in the maintenance of cognitive function (3). In addition to positive effects in both reproductive and nonreproductive organs, estrogen plays an important role in the development of uterine cancers, and both hormones have been implicated in the development of breast cancer (4–6). The critical role of estrogen in development of breast cancer is evidenced by the significant protective response observed in women after treatment with the antiestrogen, 4-hydroxy-tamoxifen (4-OHT) resulting in a 25% decrease in mortality and 45% decrease in incidence (6, 7). The conflict between positive and negative activities of these hormones has fueled a search for selective receptor modulators (SRMS) for use in hormone replacement therapy that possess the capability of harnessing the tissue selective beneficial effects of the steroids while lacking adverse activities in breast and uterus. The effects of E and P are mediated through interaction with specific intracellular receptors that are members of the nuclear receptor superfamily of transcription factors (8). Binding of the steroids to their cognate receptors induces conformational changes in receptor structure leading to receptor dimerization, posttranslational modification, and binding to specific enhancer DNA elements in the promoters of specific genes and recruitment of coregulator proteins that interact with general transcriptional machinery to elaborate hormone-triggered changes in promoter activity. In general, agonist ligands of receptors promote binding of coactivator proteins that promote transcription initiation while binding of antagonists promote interaction with corepressor proteins that facilitate transcription repression (9). Recent advances in our understanding of the molecular mechanisms of action of estrogen and progesterone receptors, together with molecular genetic approaches to examine the physiological consequences of receptor and coregulator protein ablation, have provided important insights into how physiological diversity of female steroid hormone action is achieved. Emerging from these studies is the general principle that the modular nature of receptors allows ligand, tissue and promoter specific interaction with select subsets of coregulators capable of elaborating distinct transcriptional and hence physiological responses to steroid signal. Generation of functional diversity through modular receptor proteins and distinct receptor subtypesE and P responsive tissues are initially determined by the tissue distribution of receptor proteins whose restricted spatiotemporal expression identifies tissues targeted for hormonal response. However, tissues that express receptors for estrogen and progesterone exhibit physiologically diverse responses to the same steroidal ligand. Functional diversity arises from the existence of two structurally related but nonidentical receptors for each hormone and by the ability of a single receptor subtype to elicit diverse transcriptional responses to a specific ligand. Molecular dissection of the structural and functional relationships of steroid receptors and of the mechanisms by which they interact with ligand, DNA, and the transcriptional apparatus has provided valuable information on the molecular pathways by which steroid receptors can generate functionally diverse transcriptional responses to their cognate steroid ligand. Steroid receptors including those for estrogen and progesterone have a modular protein structure consisting of distinct functional domains capable of binding steroidal ligand, dimerization of liganded receptors, interaction with hormone-responsive DNA elements, and interaction with coregulator proteins required for bridging receptors to the transcriptional apparatus (8, 9). Binding of estrogen and progestin agonists to their receptors induces conformational changes in receptor structure that promote interaction of coactivator proteins with distinct activation domains (AFs) located within both the amino and carboxy terminal regions of the receptor. Such coactivators promote chromatin remodeling and bridging with general transcription factors resulting in the formation of productive transcription initiation complexes at the receptor responsive promoter. In contrast, binding of receptor antagonist compounds induces receptor conformational changes that render AFs nonpermissive to coactivator binding and instead promote interaction with corepressor proteins that inhibit transcriptional activity of the receptor. The ability of steroid receptors to interact with a variety of coactivator and corepressor proteins, together with the differing spatiotemporal expression of coregulators, illustrate a key role of coregulators in mediating different tissue specific responses to steroidal ligand. Finally, receptors for estrogen and progesterone can be activated in the absence of steroidal ligand by phosphorylation pathways that modulate their interactions with coregulator proteins. Estrogen receptor isoformsReceptors for estrogen are expressed as two structurally related subtypes, ERα and ERβ, that are encoded by two distinct genes (10, 11). Both proteins share a high degree of amino acid conservation in their DNA binding domains (97%) and exhibit a significant but lesser degree of homology in their ligand binding domains (58%). Two functionally distinct transactivation domains have been identified in both proteins; the first (AF1) located in the poorly conserved amino terminal domain and a second (AF2) located in the ligand binding domain. AF1 and AF2 can contribute independently and synergistically to receptor transcriptional activity in response to agonist ligands and to ligand-independent phosphorylation pathways of receptor activation and their relative activities vary depending on cellular and promoter context (12–14). ERα and ERβ exhibit significant functional differences when examined under similar conditions in cell-based transactivation assays. Ligand binding profiles show both similar and distinct affinities of each receptor for different estrogen agonist and antagonist ligands (15). Transcriptional responses of each receptor to ligands with which they interact with equal affinity (including 17β-estradiol) also vary significantly due in part to sequence divergence in their AF-1 domains (16) and to a differential preference of individual subtypes for specific coactivator proteins (17). Receptor sequence divergence, however, accounts only in part for the cell- and promoter-based variations in transcriptional responses to a specific ligand. The transcription regulatory activity of either receptor in response to ligand is highly dependent on the cellular and promoter environment (12, 18). The identification of a complex group of coregulator proteins that are recruited in a cell- and promoter-specific manner to the ligand occupied estrogen receptors reflects one of the most important recent advances in our understanding of the cellular mechanisms leading to tissue diversity in transcriptional responses to estrogen (19). Superimposed upon this transcriptional diversity is the ability of different estrogen receptor agonist and antagonist ligands to induce distinct conformational changes in receptor structure, thereby generating a spectrum of transcriptional responses with altered cell and promoter dependency through ligand specific modulation of the conformational context of AF domains (20–23). In addition to providing a mechanistic explanation for ability some estrogen receptor ligands (SERMS) to elicit select tissue-specific agonist activities of estrogen, the physiological implications of these findings are that ligand-specific manipulation of coregulator interaction can be used to achieve tissue and promoter specificity in transcriptional responses to receptor. Progesterone receptor isoformsIn contrast to estrogen, receptors for progesterone are expressed as two distinct isoforms, PR-A and PR-B that arise from a single gene (24, 25). The expression of both isoforms is conserved in rodent and humans and overlaps spatiotemporally in female reproductive tissues. However, the ratios of the individual isoforms vary in reproductive tissues as a consequence of developmental (26) and hormonal status (27) and during carcinogenesis (28, 29). The PR-A and PR-B differ in that the PR-B protein contains an additional sequence of amino acids at its amino terminus that is not contained in PR-A. This PR-B-specific domain encodes a third transactivation function (AF3) that is absent from PR-A (30, 31). Recent evidence has demonstrated that the presence of AF3 allows binding of a subset of coactivators to PR-B that are not efficiently recruited by progestin-bound PR-A (32). Thus, when expressed individually in cultured cells, PR-A and PR-B display different transactivation properties that are specific to both cell type and target gene promoter context (33–36). Agonist-bound PR-B functions as a strong activator of transcription of several PR dependent promoters and in a variety of cell types in which PR-A is inactive. Further, when both isoforms are coexpressed in cultured cells, in cell and promoter contexts in which agonist bound PR-A is inactive, the PR-A can repress the activity of PR-B. This repressor capability of PR-A also extends to other steroid receptors including ERα (31, 37). Finally, the PR-A and PR-B proteins also respond differently to P antagonists (reviewed in Ref. 38). While antagonist bound PR-A is inactive, antagonist bound PR-B can be converted to a strongly active transcription factor by modulating intracellular phosphorylation pathways (39–41). Although the sequence of the ligand binding domain of the PR-A and PR-B is identical, the ability of different ligands to induce different conformational changes in PR, together with the synergistic activity of the amino and carboxy terminal activation domains (42), predicts that PR-A or PR-B selective transcriptional regulation can be achieved by manipulating ligand interactions with the carboxy terminal. Defining the physiological spectrum of steroid receptor actionThe use of genetically altered mouse mutants in which expression of individual progesterone or estrogen receptor genes has been specifically ablated has allowed direct examination of the essential roles of these receptors in mediating physiological responses to E and P. In addition to defining the individual and collective contributions of receptor subtypes to the overall repertoire of hormone action, these models facilitate examination of the contribution of specific receptor subtypes to the activities of tissue-selective receptor modulators. They have also proved a valuable means of identifying alternative pathways of steroid action that are independent of receptor activity as well as addressing the physiological significance of ligand-independent pathways of receptor activation. Finally, the receptor null mutant models serve as powerful tools to dissect the molecular genetic pathways that are regulated by these steroid receptors invivo. Tissue-selective physiological responses to estrogen through distinct receptor subtypesSelective ablation of ERα and ERβ in mice has provided definitive evidence that these receptor subtypes mediate distinct physiological responses to estrogen both within the reproductive tract and in nonreproductive tissues (11, 43–45). In general, the different roles of these subtypes are a reflection of a mostly segregated spatiotemporal distribution of each receptor. ERα is the dominant subtype expressed throughout the female reproductive tract and its ablation results in infertility due to defects in sexual behavioral expression, neuroendocrine gonadotropin regulation, ovulation, uterine function, and postpubertal mammary gland morphogenesis. The ERα-subtype also plays an essential role in male fertility and mediates many of the nonreproductive activities of estrogen including regulation of bone resorption-remodeling in females, postnatal endochondral bone growth in both sexes, cardiovascular endothelial regeneration, adipogenesis, and sexual behavior (11). In contrast to ERα, ablation of ERβ results in less severe phenotypic consequences with regard to estrogen signaling. ERβ is expressed in both the male and female reproductive tracts in a pattern largely distinct from that of ERα and its ablation results in a subfertile phenotype restricted to impaired female ovarian function (44). Its expression and activity in this tissue are complimentary to but distinct from those of ERα. Expression of ERβ has also been detected in several nonreproductive estrogen responsive tissues including bone-forming osteoblasts, epiphyseal chondrocytes, and the cardiovascular and central nervous systems. The protein was recently shown to play an essential role in regulation of cortical neuronal survival (46) and appears to contribute together with ERα to protection against cardiovascular injury (47) While the tissue-selective contributions of ERα and ERβ to estrogen and SERM signaling are still under active investigation, the distinct roles identified to date highlight the importance of these receptor subtypes in mediating tissue selective physiological responses to estrogen. The availability of ERα and ERβ knockout models has also allowed physiological testing and validation of the existence of alternative signaling pathways that are independent of either ligand or receptor. Thus, while uterotrophic responses stimulated by estrogen require functional ERα, the ability of some catechol and zenoestrogens to elicit such responses is independent of ERα (48, 49). In contrast, ERα is an essential mediator of proliferative responses that are stimulated in this tissue by epidermal growth factor acting in the absence of estrogen (50). This latter observation has provided an important physiological validation of the ligand-independent activation of estrogen receptors previously observed in cell based transactivation assays. Tissue selectivity through progesterone receptor isoformsThe differences in transcriptional activities and coregulator interactions between the PR-A and PR-B observed in vitro predicted that these proteins also may mediate different physiological responses to progesterone. In addition, the selective ability of PR-A to inhibit transcriptional responses induced by both PR-B and the estrogen receptors suggested that PR-A has the capacity to diminish overall progesterone responsiveness in certain tissues as well as contribute to the antiestrogenic activities of progesterone previously observed in the uterus. Null mutation of the PR gene encoding both isoforms has provided evidence of an essential role of PRs in a variety of female reproductive and nonreproductive activities (51). Female mice lacking both PRs exhibit impaired sexual behavior, neuroendocrine gonadotropin regulation, anovulation, uterine dysfunction, and impaired ductal branching morphogenesis and lobuloalveolar differentiation of the mammary gland. PRs also play an essential role in regulation thymic involution during pregnancy and in the cardiovascular system through regulation of endothelial cell proliferation (52, 53). Receptors for progesterone have also been identified in the central nervous system and bone where progesterone has been implicated in both cognitive function and bone maintenance. However, the essential role of PRs in these regions has not yet been confirmed. Recent studies have begun to address the individual contributions of the PR-A and PR-B proteins to the physiological actions of progesterone using mouse mutants in which expression of the PR-A (PRAKO) or PR-B (PRBKO) isoform has been selectively ablated. Analysis of the phenotypic consequences of these mutations on female reproductive function has provided physiological proof of principle that the distinct transcriptional responses to PR-A and PR-B observed in cell-based transactivation assays are indeed reflected in an ability of the individual isoforms to elicit distinct physiological responses to progesterone. In PRAKO mice (54), the PR-B isoform functions in a tissue-specific manner to mediate a subset of the reproductive functions of PRs. Ablation of PR-A does not affect responses of the mammary gland or thymus to P but results in severe abnormalities in ovarian and uterine function. Surprisingly, the absence of PR-A in PRAKO uteri revealed an unexpected P dependent proliferative activity of PR-B in the epithelium and demonstrated that PR-A is essential to diminish both progesterone (acting via PRB) and estrogen-mediated proliferative responses in this tissue. The observation that PR-A is essential to inhibit estrogen induced proliferation in the uterus is consistent with previous observations that agonist bound PR-A is capable of inhibiting estrogen-dependent transcriptional activation in cell-based transactivation assays (37). Notably, this inhibitory activity of PRA was tissue specific and did not extend to the mammary gland where both PR-A and PR-B act as proliferative mediators of P. Consistent with the distinct tissue- and promoter-specific activities of PR-A and PR-B observed in tissue culture studies, the tissue-selective activities of PR-B observed in PRAKO mice were associated with an ability of this isoform to regulate a subset of progesterone responsive target genes rather than to differences in its spatiotemporal expression relative to the PR-A isoform (54). In contrast to the reproductive defects observed in PRAKO mice, more recent studies using PRBKO mice have shown that ablation of PR-B does not affect either ovarian, uterine, or thymic responses to progesterone but results in reduced mammary ductal morphogenesis (Jericevic, B., and O. M. Conneely, unpublished observations). Thus, PR-A is both necessary and sufficient to elicit these P-dependent reproductive responses while the PR-B isoform is required to elicit normal proliferative responses of the mammary gland to P. From a mechanistic standpoint, the differences in physiological activities observed between the PR-A and PR-B isoforms provides an important illustration of the key role played by the amino terminal AF domains in distinguishing tissue specific responses to steroidal ligand. The results demonstrate that the inclusion or deletion of the N-terminal AF3 domain in PR is sufficient to alter tissue specific physiological responses to P. Contribution of steroid receptor coregulators to physiological diversity of hormonal responseThe characterization and mode of action of coregulator proteins that mediate the transcriptional activity of steroid receptors have been intensely examined in recent years. Agonist ligand or ligand-independent activation of receptors is associated with recruitment of a complex group of coactivators including nucleosome-disrupting histone acetyltransferases (SRC family members, PCAF and P300), mediator proteins that bridge receptor complexes with the general transcription factor complexes (e.g. DRIP/TRAP220/ARC, and mediator), an RNA helicase, p68 and components of the ubiquitin proteosome degradation system including the ubiquitin ligases, E6AP and RPF1(9, 14, 55, 56). A growing number of corepressors associated with antagonist ligand repression of transcriptional activation have also been identified including the histone deacetylases, N-COR and SMRT (57, 58) and the estrogen receptor interacting proteins RIP140 (59) and REA (60). Considering the complex array of coregulator proteins that can interact with both estrogen and progesterone receptors, tissue selective expression of distinct subsets of coregulator proteins would be expected to strongly influence receptor dependent biological responses in specific tissues. Results from recent studies on the comparative spatiotemporal expression of coregulators and steroid receptors in mammalian tissues, together with the generation of knockout mouse models carrying null mutations of several coregulator proteins, have provided a key proof of concept of the essential role of coregulator proteins in mediating tissue selective physiological responses to steroidal ligand. It is becoming apparent that the spatiotemporal expression of some coregulator proteins in steroid responsive tissues is both developmentally and hormonally controlled. For example, the expression of coactivator SRC-1 is dissociated from estrogen receptor-expressing cells during postpubertal mammary gland morphogenesis but becomes colocalized with ER-positive cells during pregnancy (61, 62). A growing number of recent reports have also associated aberrant expression of coregulator proteins with the development of breast cancer. Significantly, these reports reveal a developing pattern of increased coactivator levels associated with tumorigenesis while the expression of corepressors is significantly decreased. For example, levels of CBP, TRAP220, and the SRC family members, SRC-2/TIF2 and AIB-1/SRC-3 are all elevated breast tumors (63, 64). However, most notable among these is AIB-1/SRC-3, which is overexpressed in 60% of human breast cancers (65). Conversely, levels of the corepressor, N-Cor, are decreased in invasive relative to intraductal carcinomas (64) and with the development of tamoxifen resistance in a mouse model of breast cancer (66). Definitive evidence of the essential role of specific coregulators in mediation of tissue-specific responses to estrogen and progesterone has recently been provided by genetic ablation of a few coregulator proteins in mice. Analysis of the reproductive phenotypes of mice carrying a null mutation of SRC-1 (67) and SRC-3 (68) indicate that these coactivators regulate mostly distinct physiological activities that are due to a generally segregated spatiotemporal expression pattern of the two proteins. However, with regard to their role in E- and P-dependent reproductive physiology, deletion of either coactivator results in a partial hormone resistance in mammary gland developmental responses to E and P, indicating essential nonredundant roles for both proteins in this tissue. In contrast, only SRC-1 is expressed in the uterus and its expression is essential to elicit full growth and differentiative responses of this tissue to E and P, whereas uterine function is unaffected by deletion of SRC-3. Validation of the essential role of steroid receptor corepressors in mediating the transcriptional activity of estrogen receptors has also recently been provided by gene targeting approaches. Analysis of the transcriptional responses of mouse embryonic fibroblasts carrying a null mutation of N-CoR to the estrogen receptor antagonist, 4-OHT, demonstrated that this protein was essential to mediate the inhibitory activity of the antagonist. Ablation of N-CoR resulted in a conversion of 4-OHT to a full receptor agonist (69). Finally, ablation of the corepressor, RIP140, in mice resulted ovulatory dysfunction and an ovarian phenotype partially overlapping that previously observed in PRKO mice, whereas uterine implantation was unaffected (70). However, while the phenotype of RIP140 null mice supports a tissue-specific contribution of the protein to reproductive function, a direct connection between the anovulatory phenotype and the corepressor activity of RIP140 remains to be established. ConclusionsDuring the past decade we have witnessed outstanding progress in our understanding of the molecular pathways by which steroid receptors elicit diverse physiological responses to hormonal signals. It is clear that tissue and promoter selectivity in hormone action is determined not only by the tissue-selective expression of distinct receptor subtypes but also of a complex group of receptor interacting coregulator proteins whose function is essential in establishing the diverse repertoire of transcriptional responses to hormone. The central role of coregulators in mediating physiological responses to estrogen and progesterone has only recently begun to be appreciated. The availability of transgenic and knock-out models to facilitate examination of the physiological roles of individual coregulators, together with the use of differential gene array technologies to identify tissue-specific downstream targets of the hormonal response, should facilitate dissection of the steroid-dependent molecular genetic pathways influenced by specific coregulators. From the limited physiological analysis carried out to date, it is becoming apparent that abnormal coregulator function may contribute to a variety of hormone- related diseases including steroid resistance syndromes, reproductive dysfunction, and tumorigenesis. Continued efforts to alter coregulator recruitment to receptors by manipulation of receptor conformation using novel ligands together with a clearer understanding of the tissue-specific molecular pathways influenced by specific coregulators should facilitate the development of new optimized tissue specific ligands for hormonal therapy. 1
Turner RT ,Riggs BL ,Spelsberg TC 1994 Skeletal effects of estrogen. Endocr Rev 15 : 275 – 300 2 Iafrati MD ,Karas RH ,Aronovitz M ,Kim S ,Sullivan TRJ ,Lubahn DB ,O’Donnell TFJ ,Korach KS ,Mendelsohn, ME 1997 Estrogen inhibits the vascular injury response in estrogen receptorα -deficient mice. Nature Med 3 : 545 – 548 3 Tang MX ,Jacobs D ,Stern Y ,Marder K ,Schofield P ,Gurland B ,Andre H ,Mayeux, R 1996 Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease. Lancet 348 : 429 – 432 4 Jordan VC ,Murphy, CS 1990 Endocrine pharmacology of antiestrogens as antitumor agents. Endocr Rev 11 : 578 – 610 5 Horwitz K ,Clarke C 1998 Estrogens and progestins in mammary development and neoplasia. J Mammary Gland Biol Neoplasia 3 : 1 – 2 6 Jordan VC ,Morrow M 1999 Tamoxifen, raloxifene, and the prevention of breast cancer.Endocr Rev 20 : 253 – 278 7 Peto R ,Boreham J ,Clarke M ,Davies C ,Beral V 2000UK and USA breast cancer deaths down 25% in year at ages 20–69 years.Lancet 355 : 1822 8
Tsai MJ ,O’Malley BW 1994 Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu Rev Biochem 63 : 451 – 486 9 McKenna NJ ,Xu J ,Nawaz Z ,Tsai SY ,Tsai MJ ,O’Malley BW 1999 Nuclear receptor coactivators: multiple enzymes, multiple complexes, multiple functions. J Steroid Biochem Mol Biol 69 : 3 – 12 10 Kuiper GG ,Enmark E ,Pelto-Huikko M ,Nilsson S ,Gustafsson JA 1996 Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 93 : 5925 – 5930 11 Couse JF ,Korach, KS 1999 Estrogen receptor null mice: what have we learned and where will they lead us? [published erratum appears in Endocr Rev 1999 Aug: (20):459], Endocr Rev 20 : 358 – 417 12 Tzukerman MT ,Esty A ,Santiso-Mere D ,Danielian P ,Parker MG ,Stein RB ,Pike JW ,McDonnell DP 1994 Human estrogen receptor transactivational capacity is determined by both cellular and promoter context and mediated by two functionally distinct intramolecular regions. Mol Endocrinol 8 : 21 – 30 13
Kraus WL ,McInerney EM ,Katzenellenbogen BS 1995 Ligand-dependent, transcriptionally productive association of the amino- and carboxyl-terminal regions of a steroid hormone nuclear receptor. Proc Natl Acad Sci USA 92 : 12314 – 12318 14 Endoh H ,Maruyama K ,Masuhiro Y ,Kobayashi Y ,Goto M ,Tai H ,Yanagisawa J ,Metzger D ,Hashimoto S ,Kato S 1999 Purification and identification of p68 RNA helicase acting as a transcriptional coactivator specific for the activation function 1 of human estrogen receptor α. Mol Cell Biol 19 : 5363 – 5372 15 Kuiper GG ,Carlsson B ,Grandien K ,Enmark E ,Haggblad J ,Nilsson S ,Gustafsson JA 1997 Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptorsα and β. Endocrinology 138 : 863 – 870 16 McInerney EM ,Weis KE ,Sun J ,Mosselman S ,Katzenellenbogen BS 1998 Transcription activation by the human estrogen receptor subtype beta (ER β) studied with ER β and ER α receptor chimeras. Endocrinology 139 : 4513 – 4522 17 Suen CS ,Berrodin TJ ,Mastroeni R ,Cheskis BJ ,Lyttle CR ,Frail, DE 1998 A transcriptional coactivator, steroid receptor coactivator-3, selectively augments steroid receptor transcriptional activity. J Biol Chem 273 : 27645 – 27653 18 Katzenellenbogen BS ,Montano MM ,Ediger TR ,Sun J ,Ekena K ,Lazennec G ,Martini PG ,McInerney EM ,Delage-Mourroux R ,Weis K ,Katzenellenbogen, JA 2000 Estrogen receptors: selective ligands, partners, and distinctive pharmacology. Rec Prog Hormone Res 55 : 163 – 193 19 McKenna NJ ,Lanz RB ,O’Malley BW 1999 Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev 20 : 321 – 344 20 McDonnell DP ,Clemm DL ,Hermann T ,Goldman ME ,Pike JW 1995 Analysis of estrogen receptor function in vitro reveals three distinct classes of antiestrogens. Mol Endocrinol 9 : 659 – 669 21 Brzozowski AM ,Pike AC ,Dauter Z ,Hubbard RE ,Bonn T ,Engstrom O ,Ohman L ,Greene GL ,Gustafsson JA ,Carlquist M 1997 Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389 : 753 – 758 22 Paige LA ,Christensen DJ ,Gron H ,Norris JD ,Gottlin EB ,Padilla KM ,Chang CY ,Ballas LM ,Hamilton PT ,McDonnell DP ,Fowlkes DM 1999 Estrogen receptor (ER) modulators each induce distinct conformational changes in ER α and ER β. Proc Natl Acad Sci USA 96 : 3999 – 4004 23 Norris JD ,Paige LA ,Christensen DJ ,Chang CY ,Huacani MR ,Fan D ,Hamilton PT ,Fowlkes DM ,McDonnell DP 1999 Peptide antagonists of the human estrogen receptor. Science 285 : 744 – 746 24
Conneely OM ,Kettelberger DM ,Tsai MJ ,Schrader WT ,O’Malley BW 1989 The chicken progesterone receptor A and B isoforms are products of an alternate translation initiation event. J Biol Chem 264 : 14062 – 14064 25 Kastner P ,Krust A ,Turcotte B ,Stropp U ,Tora L ,Gronemeyer H ,Chambon P 1990 Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. Embo J 9 : 1603 – 1614 26 Shyamala G ,Schneider W ,Schott D 1990 Developmental regulation of murine mammary progesterone receptor gene expression. Endocrinology 126 : 2882 – 2889 27 Duffy DM ,Wells TR ,Haluska GJ ,Stouffer RL 1997 The ratio of progesterone receptor isoforms changes in the monkey corpus luteum during the luteal phase of the menstrual cycle. Biol Reprod 57 : 693 – 699 28 Brandon DD ,Bethea CL ,Strawn EY ,Novy MJ ,Burry KA ,Harrington MS ,Erickson TE ,Warner C ,Keenan EJ ,Clinton GM 1993 Progesterone receptor messenger ribonucleic acid and protein are overexpressed in human uterine leiomyomas. Am J Obstet Gynecol 169 : 78 – 85 29 Graham JD ,Yeates C ,Balleine RL ,Harvey SS ,Milliken JS ,Bilous AM ,Clarke CL 1996 Progesterone receptor A, and B protein expression in human breast cancer. J Steroid Biochem Mol Biol 56 : 93 – 98 30 Sartorius CA ,Melville MY ,Hovland AR ,Tung L ,Takimoto GS ,Horwitz KB 1994 A third transactivation function (AF3) of human progesterone receptors located in the unique N-terminal segment of the B-isoform. Mol Endocrinol 8 : 1347 – 1360 31 Wen DX ,Xu YF ,Mais DE ,Goldman ME ,McDonnell DP 1994 The A and B isoforms of the human progesterone receptor operate through distinct signaling pathways within target cells. Mol Cell Biol 14 : 8356 – 8364 32 Giangrande PH ,Kimbrel EA ,Edwards DP ,McDonnell DP 2000 The opposing transcriptional activities of the two isoforms of the human progesterone receptor are due to differential cofactor binding. Mol Cell Biol 20 : 3102 – 3115 33 Tora L ,Gronemeyer H ,Turcotte B ,Gaub MP ,Chambon P 1988 The N-terminal region of the chicken progesterone receptor specifies target gene activation. Nature 333 : 185 – 188 34 Meyer ME ,Quirin-Stricker C ,Lerouge T ,Bocquel MT ,Gronemeyer H 1992 A limiting factor mediates the differential activation of promoters by the human progesterone receptor isoforms. J Biol Chem 267 : 10882 – 10887 35 Vegeto E ,Shahbaz MM ,Wen DX ,Goldman ME ,O’Malley BW ,McDonnell DP 1993 Human progesterone receptor A form is a cell- and promoter-specific repressor of human progesterone receptor B function. Mol Endocrinol 7 : 1244 – 1255 36 Hovland AR ,Powell RL ,Takimoto GS ,Tung L ,Horwitz KB 1998 An N-terminal inhibitory function IF, suppresses transcription by the A-isoform but not the B-isoform of human progesterone receptors. J Biol Chem 273 : 5455 – 5460 37
McDonnell DP ,Shahbaz MM ,Vegeto E ,Goldman ME 1994 The human progesterone receptor A-form functions as a transcriptional modulator of mineralocorticoid receptor transcriptional activity. J Steroid Biochem Mol Biol 48 : 425 – 432 38 Giangrande PH ,McDonnell DP 1999 The A and B isoforms of the human progesterone receptor: two functionally different transcription factors encoded by a single gene. Recent Prog Horm Res 54 : 291 – 313 39 Sartorius CA ,Groshong SD ,Miller LA ,Powell RL ,Tung L ,Takimoto GS ,Horwitz KB 1994 New T47D breast cancer cell lines for the independent study of progesterone B- and A-receptors: only antiprogestin-occupied B- receptors are switched to transcriptional agonists by cAMP. Cancer Res 54 : 3868 – 3877 40 Musgrove EA ,Hamilton JA ,Lee CS ,Sweeney KJ ,Watts CK ,Sutherland RL 1993 Growth factor, steroid, and steroid antagonist regulation of cyclin gene expression associated with changes in T-47D human breast cancer cell cycle progression. Mol Cell Biol 13 : 3577 – 3587 41 Beck CA ,Weigel NL ,Moyer ML ,Nordeen SK ,Edwards DP 1993 The progesterone antagonist RU486 acquires agonist activity upon stimulation of cAMP signaling pathways. Proc Natl Acad Sci USA 90 : 4441 – 4445 42 Tetel MJ ,Giangrande PH ,Leonhardt SA ,McDonnell DP ,Edwards DP 1999 Hormone-dependent interaction between the amino- and carboxyl-terminal domains of progesterone receptor in vitro and in vivo. Mol Endocrinol 13 : 910 – 924 43 Lubahn DB ,Moyer JS ,Golding TS ,Couse JF ,Korach KS ,Smithies O 1993 Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc Natl Acad Sci USA 90 : 11162 – 11166 44 Krege JH ,Hodgin JB ,Couse JF ,Enmark E ,Warner M ,Mahler JF ,Sar M ,Korach KS ,Gustafsson JA ,Smithies O 1998 Generation and reproductive phenotypes of mice lacking estrogen receptor β. Proc Natl Acad Sci USA 95 : 15677 – 15682 45 Dupont S ,Krust A ,Gansmuller A ,Dierich A ,Chambon P ,Mark M 2000 Effect of single and compound knockouts of estrogen receptors alpha (ERα) and β (ERβ) on mouse reproductive phenotypes. Development 127 : 4277 – 4291 46 Wang L ,Andersson S ,Warner M ,Gustafsson JA 2001 Morphological abnormalities in the brains of estrogen receptor β knockout mice. Proc Natl Acad Sci USA 98 : 2792 – 2796 47 Mendelsohn ME 2000 Mechanisms of estrogen action in the cardiovascular system. J Steroid Biochem Mol Biol 74 : 337 – 343 48 Das SK ,Taylor JA ,Korach KS ,Paria BC ,Dey SK ,Lubahn DB 1997 Estrogenic responses in estrogen receptor-α deficient mice reveal a distinct estrogen signaling pathway. Proc Natl Acad Sci USA 94 : 12786 – 12791 49 Ghosh D ,Taylor JA ,Green JA ,Lubahn DB 1999 Methoxychlor stimulates estrogen-responsive messenger ribonucleic acids in mouse uterus through a non-estrogen receptor (non-ER) α and non-ERβ mechanism. Endocrinology 140 : 3526 – 3533 50 Curtis SW ,Washburn T ,Sewall C ,DiAugustine R ,Lindzey J ,Couse JF ,Korach, K 1996 Physiological coupling of growth factor and steroid receptor signaling pathways: estrogen receptor knockout mice lack estrogen-like response to epidermal growth factor. Proc Natl Acad Sci USA 93 : 12626 – 12630 51 Lydon JP ,DeMayo FJ ,Funk CR ,Mani SK ,Hughes AR ,Montgomery Jr CA ,Shyamala G ,Conneely OM ,O’Malley BW 1995 Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev 9 : 2266 – 2278 52 Tibbetts TA ,DeMayo F ,Rich S ,Conneely OM ,O’Malley BW 1999 Progesterone receptors in the thymus are required for thymic involution during pregnancy and for normal fertility. Proc Natl Acad Sci USA 96 : 12021 – 12026 53 Vazquez F ,Rodriguez-Manzaneque JC ,Lydon JP ,Edwards DP ,O’Malley BW ,Iruela-Arispe, ML 1999 Progesterone regulates proliferation of endothelial cells. J Biol Chem 274 : 2185 – 2192 54 Mulac-Jericevic B ,Mullinax RA ,DeMayo FJ ,Lydon JP ,Conneely OM 2000 Subgroup of reproductive functions of progesterone mediated by progesterone receptor-B isoform. Science 289 : 1751 – 1754 55 Nawaz Z ,Lonard DM ,Smith CL ,Lev-Lehman E ,Tsai SY ,Tsai MJ ,O’Malley BW 1999 The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily. Mol Cell Biol 19 : 1182 – 1189 56 Imhof MO ,McDonnell DP 1996 Yeast RSP5 and its human homolog hRPF1 potentiate hormone dependent activation of transcription by human progesterone and glucocorticoid receptors. Mol Cell Biol 16 : 2594 – 2605 57 Horlein AJ ,Naar AM ,Heinzel T ,Torchia J ,Gloss B ,Kurokawa R ,Ryan A ,Kamei Y ,Soderstrom M ,Glass CK ,Rosenfeld M 1995 Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature 377 : 397 – 404 58 Chen JD ,Evans RM 1995 A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 377 : 454 – 457 59 Cavailles V ,Dauvois S ,L’Horset F ,Lopez G ,Hoare S ,Kushner PJ ,Parker MG 1995 Nuclear factor RIP140 modulates transcriptional activity by the oestrogen receptor. EMBO J 14 : 3741 – 3751 60 Montano MM ,Ekena K ,Delage-Mourroux R ,Chang W ,Martini P ,Katzenellenbogen BS 1999 An estrogen receptor-selective coregulator that potentiates the effectiveness of antiestrogens and represses the activity of estrogens. Proc Natl Acad Sci USA 96 : 6947 – 6952 61 Shim WS ,DiRenzo J ,DeCaprio JA ,Santen RJ ,Brown M ,Jeng MH 1999 Segregation of steroid receptor coactivator-1 from steroid receptors in mammary epithelium. Proc Natl Acad Sci USA 96 : 208 – 213 62 Shim W-S ,Chang L-Y ,Zhang Q ,Turner MA ,Brown M ,Jeng M-H Segregation and colocalization of steroid receptor coactivators with estrogen receptor α during mammary gland development , Program of the 82nd Annual Meeting of The Endocrine Society , Toronto, Canada , p 343 (Abstract 1423) 63 Zhu Y ,Qi C ,Jain S ,Le Beau MM ,Espinosa R ,Atkins GB ,Lazar MA ,Yeldandi AV ,Rao MS ,Reddy JK 1999 Amplification and overexpression of peroxisome proliferator-activated receptor binding protein (PBP/PPARBP) gene in breast cancer. Proc Natl Acad Sci USA 96 : 10848 – 10853 64 Kurebayashi J ,Otsuki T ,Kunisue H ,Tanaka K ,Yamamoto S ,Sonoo H 2000 Expression levels of estrogen receptor-α, estrogen receptor-β, coactivators, and corepressors in breast cancer. Clin Cancer Res 6 : 512 – 518 65
Anzick SL ,Kononen J ,Walker RL ,Azorsa DO ,Tanner MM ,Guan XY ,Sauter G ,Kallioniemi OP ,Trent JM ,Meltzer PS 1997 AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science 277 : 965 – 968 66 Lavinsky RM ,Jepson K ,Heinzel T ,Torchia J ,Mullen TM ,Schiff R ,Del-Rio AL ,Ricote M ,Ngo S ,Gemsch J ,Hilsenbeck SG ,Osborne CK ,Glass CK ,Rosenfeld MG ,Rose DW 1998 Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes. Proc Natl Acad Sci USA 95 : 2920 – 2925 67 Xu J ,Qiu Y ,DeMayo FJ ,Tsai SY ,Tsai MJ ,O’Malley BW 1998 Partial hormone resistance in mice with disruption of the steroid receptor coactivator-1 (SRC-1) gene. Science 279 : 1922 – 1925 68 Xu J ,Liao L ,Ning G ,Yoshida-Komiya H ,Deng C ,O’Malley BW 2000 The steroid receptor coactivator SRC-3 (p/CIP/RAC3/AIB1/ACTR/TRAM-1) is required for normal growth, puberty, female reproductive function, and mammary gland development. Proc Natl Acad Sci USA 97 : 6379 – 6384 69 Jepsen K ,Hermanson O ,Onami TM ,Gleiberman AS ,Lunyak V ,McEvilly RJ ,Kurokawa R ,Kumar V ,Liu F ,Seto E ,Hedrick SM ,Mandel G ,Glass CK ,Rose DW ,Rosenfeld MG 2000 Combinatorial roles of the nuclear receptor corepressor in transcription and development. Cell 102 : 753 – 763 70
White R ,Leonardsson G ,Rosewell I ,Jacobs MA ,Milligan S ,Parker M 2000 The nuclear receptor co-repressor Nrip1 (RIP140) is essential for female fertility. Nature Medicine 6 : 1368 – 1373 Copyright © 2001 by The Endocrine Society Copyright © 2001 by The Endocrine Society CitationsViewsAltmetricEmail alertsRelated articles in PubMedCiting articles via
More from Oxford Academic What is the steroid hormone which is produced by the ovaries after ovulation?Progesterone is an endogenous steroid hormone that is commonly produced by the adrenal cortex as well as the gonads, which consist of the ovaries and the testes. Progesterone is also secreted by the ovarian corpus luteum during the first ten weeks of pregnancy, followed by the placenta in the later phase of pregnancy.
Is estrogen a steroid hormone?Estrogens are a group of steroid hormones that regulate reproductive function and secondary sex characteristics in the female, including breast development.
Is progesterone a steroid?Progesterone is a steroid hormone traditionally linked with female fertility and pregnancy. In current reproductive medicine, progesterone and its analogues play crucial roles.
Which of the following are steroid hormones secreted by the ovaries quizlet?The female gonads (ovaries) produce two groups of steroid hormones: estrogens and progesterone.
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