Mapping and Characterization of the Functional Domains Responsible for the Differential Activity of the A and B Isoforms of the Human Progesterone Receptor

In humans, the biological response to progesterone is mediated by two distinct forms of the progesterone receptor (human (h) PR-A, 94 kDa and hPR-B, 114 kDa). These two isoforms are transcribed from distinct estrogen-inducible promoters within a single copy PR gene; the only difference between them is that the first 164 amino acids of hPR-B (B-upstream sequence) are absent in hPR-A. In most cell lines such as MCF-7 (human breast cancer cells), CV-1 (monkey kidney fibroblasts), and HeLa (human cervical carcinoma cells), hPR-A functions as a transcriptional repressor, whereas hPR-B functions as a transcriptional activator of progesterone-responsive genes. Interestingly, in these cell contexts, hPR-A also acts as a trans-dominant repressor of the transcriptional activity of other steroid hormone receptors.In contrast to hPR-A, which functions predominantly as a ligand-dependent transcriptional repressor, we show in this study that the A isoform of the chicken PR (cPR-A) lacks this trans-dominant repressor function and is a transcriptional activator in all contexts examined. By constructing chimeras between the N-terminal domains of the chicken and human PR, we mapped the trans-dominant repressor function of hPR-A to the first 140 amino acids of the protein. Notably, when this 140-amino acid “repressor” domain is placed onto chicken PR-A, the activity of the latter changes from a transcriptional activator to a repressor. Interestingly, however, this “repressor domain” is necessary, but not sufficient, for trans-repression as it is inactive when it is tethered to a heterologous protein. This suggests that the trans-repression function is comprised not only of the repressor domain of hPR-A but also requires the context of the receptor to function. The identification of a discrete inhibitory region within hPR-A which is transferable to another receptor implies that this region interacts with a set of transcription factors or adaptors that are distinct from those recognized by hPR-B, the identification of which will be required to define the mechanism by which hPR-A modulates steroid hormone receptor transcriptional activity. Thus, although chickens and humans both produce two very similar forms of the progesterone receptor, it is clear from these studies that the mechanism of action of progesterone in these two systems is quite different. In humans, the biological response to progesterone is mediated by two distinct forms of the progesterone receptor (human (h) PR-A, 94 kDa and hPR-B, 114 kDa). These two isoforms are transcribed from distinct estrogen-inducible promoters within a single copy PR gene; the only difference between them is that the first 164 amino acids of hPR-B (B-upstream sequence) are absent in hPR-A. In most cell lines such as MCF-7 (human breast cancer cells), CV-1 (monkey kidney fibroblasts), and HeLa (human cervical carcinoma cells), hPR-A functions as a transcriptional repressor, whereas hPR-B functions as a transcriptional activator of progesterone-responsive genes. Interestingly, in these cell contexts, hPR-A also acts as a trans-dominant repressor of the transcriptional activity of other steroid hormone receptors. In contrast to hPR-A, which functions predominantly as a ligand-dependent transcriptional repressor, we show in this study that the A isoform of the chicken PR (cPR-A) lacks this trans-dominant repressor function and is a transcriptional activator in all contexts examined. By constructing chimeras between the N-terminal domains of the chicken and human PR, we mapped the trans-dominant repressor function of hPR-A to the first 140 amino acids of the protein. Notably, when this 140-amino acid “repressor” domain is placed onto chicken PR-A, the activity of the latter changes from a transcriptional activator to a repressor. Interestingly, however, this “repressor domain” is necessary, but not sufficient, for trans-repression as it is inactive when it is tethered to a heterologous protein. This suggests that the trans-repression function is comprised not only of the repressor domain of hPR-A but also requires the context of the receptor to function. The identification of a discrete inhibitory region within hPR-A which is transferable to another receptor implies that this region interacts with a set of transcription factors or adaptors that are distinct from those recognized by hPR-B, the identification of which will be required to define the mechanism by which hPR-A modulates steroid hormone receptor transcriptional activity. Thus, although chickens and humans both produce two very similar forms of the progesterone receptor, it is clear from these studies that the mechanism of action of progesterone in these two systems is quite different. The progesterone receptor (PR) 1The abbreviations used are: PR, progesterone receptor; c, chicken; h, human; HSP, heat shock protein; PRE, progesterone response elements; DBD, DNA-binding domain; HBD, hormone-binding domain; GR, glucocorticoid receptor; ER, estrogen receptor; ERE, ER element; PCR, polymerase chain reaction; CMV, cytomegalovirus; BUS, B-upstream segment; 17β-E2, 17β-estradiol. 1The abbreviations used are: PR, progesterone receptor; c, chicken; h, human; HSP, heat shock protein; PRE, progesterone response elements; DBD, DNA-binding domain; HBD, hormone-binding domain; GR, glucocorticoid receptor; ER, estrogen receptor; ERE, ER element; PCR, polymerase chain reaction; CMV, cytomegalovirus; BUS, B-upstream segment; 17β-E2, 17β-estradiol. belongs to the superfamily of intracellular receptors that mediate the nuclear effects of steroid hormones, thyroid hormone, and the non-nutritional vitamins A and D (1Evans R.M. Science. 1988; 240: 889-895Crossref PubMed Scopus (6291) Google Scholar). The mechanism of action of PR is similar to that of the other steroid receptors. In the absence of ligand the receptor is transcriptionally inactive and remains sequestered in a large complex of heat shock proteins (HSPs) as follows: HSP-90, HSP-70, and P59 (2Smith D.F. Faber L.E. Toft D.O. J. Biol. Chem. 1990; 265: 3996-4003Abstract Full Text PDF PubMed Google Scholar, 3Bagchi M.K. Tsai S.-Y. Tsai M.-J. O'Malley B.W. Mol. Cell. Biol. 1991; 11: 4998-5004Crossref PubMed Scopus (50) Google Scholar, 4Pratt W.B. Hutchinson K.A. Scherrer L.W. Trends Endocrinol. Metab. 1992; 3: 326-333Abstract Full Text PDF PubMed Scopus (33) Google Scholar). Upon ligand binding, the receptor undergoes a distinct change in conformation (5DeMarzo A.M. Beck C.A. Onate S.A. Edwards D.P. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 72-76Crossref PubMed Scopus (106) Google Scholar) that results in the dissociation of a monomeric receptor from the heat shock complex (5DeMarzo A.M. Beck C.A. Onate S.A. Edwards D.P. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 72-76Crossref PubMed Scopus (106) Google Scholar, 6Renoir J.M. Radanyi C. Jung-Testas I. Faber L.E. Baulieu E.E. J. Biol. Chem. 1990; 265: 14402-14406Abstract Full Text PDF PubMed Google Scholar). Liganded receptors then spontaneously dimerize and bind to DNA via specific progesterone response elements (PREs) located within the regulatory regions of target genes (7Bagchi M.K. Elliston J.F. Tsai S.Y. Edwards D.P. Tsai M.-J. O'Malley B.W. Mol. Endocrinol. 1988; 2: 1221-1229Crossref PubMed Scopus (65) Google Scholar). The binding of either an agonist, or of most antagonists, converts the receptor into a DNA binding competent form (8Beekman J.M. Allan G.F. Tsai S.Y. Tsai M.-J. O'Malley B.W. Mol. Endocrinol. 1993; 7: 1266-1274PubMed Google Scholar). However, only agonist-bound PR receptors are of transcriptional when to progesterone receptor is similar to that of other steroid receptors in that it a DNA-binding domain a hormone-binding domain the steroid receptors such as PR and glucocorticoid receptor and an N-terminal domain which is the most region the A. J. J. 1990; PubMed Scopus Google Scholar). The regions for receptor and with heat shock proteins are also located the within the of PR B.W. Mol. Endocrinol. 1990; PubMed Scopus Google Scholar). the also of the transcriptional domains J. 1992; 11: PubMed Scopus Google Scholar). The other transcriptional is located in the of the A. J. J. 1990; PubMed Scopus Google Scholar, C. J. Biol. Chem. 1992; Full Text PDF PubMed Google human PR is in that it as two isoforms hPR-B and hPR-A PubMed Scopus Google Scholar). The human is a form of hPR-B the first 164 N-terminal amino These two isoforms are transcribed from distinct estrogen-inducible promoters within a single copy PR A. U. J. 1990; PubMed Scopus Google Scholar). isoforms in most with the of the PR only as the isoform A. C. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). The of the two PR isoforms in forms similar DNA and ligand binding PubMed Scopus Google Scholar). However, progesterone-responsive transcription systems in that hPR-A and hPR-B are not A. J. J. 1990; PubMed Scopus Google Scholar, A. U. J. 1990; PubMed Scopus Google Scholar, O'Malley B.W. D.P. Mol. Endocrinol. 1993; 7: PubMed Scopus Google Scholar). hPR-B functions as a transcriptional activator in most contexts, whereas in most hPR-A not transcription but functions as a trans-dominant repressor of hPR-B, glucocorticoid receptor receptor, receptor, and estrogen receptor transcriptional activity O'Malley B.W. D.P. Mol. Endocrinol. 1993; 7: PubMed Scopus Google Scholar, D.P. J. Biol. Chem. Full Text PDF PubMed Google Scholar, D.P. Biol. Google the human receptor, both the A and isoforms of the chicken PR as of progesterone-responsive genes in Toft D.O. O'Malley B.W. PubMed Scopus Google Scholar, 1988; PubMed Scopus Google Scholar, C. J. Mol. Biol. 1991; PubMed Scopus Google Scholar). Thus, although the of the and hPR-A are quite are quite different. A of the amino acid that and hPR-A are very most of the of the protein; however, are in we that the for the of and hPR-A within the that by and chimeras between the two proteins that the within hPR-A required for trans-repression be this we show that the N-terminal 140-amino acid region of hPR-A is necessary, but not sufficient, for trans-repression of ER transcriptional activity. In that this repressor region of hPR-A requires other domains within the receptor to form the for is that this is required to a required for transcriptional of progesterone to estrogen action in estrogen by ER the estrogen in 1990; 11: PubMed Scopus Google and ER action the The mechanism of progesterone action ER first in the These studies that ER of progesterone PubMed Scopus Google Scholar). it that ER in the of the be by J. Endocrinol. Metab. PubMed Scopus Google Scholar). studies in breast cancer Mol. Endocrinol. 3: PubMed Scopus Google Scholar, J. Mol. Endocrinol. 1990; PubMed Scopus Google Scholar) a in ER to ER a of of transcription of the ER progesterone is also of regulatory although the mechanism of this is not that PR ER transcriptional activity by a transcription for ER action D.P. J. Biol. Chem. Full Text PDF PubMed Google D.P. Mol. Cell. Biol. PubMed Scopus Google Scholar, Mol. Cell. Biol. PubMed Scopus Google Scholar, J. Biol. Chem. Full Text PDF PubMed Google Scholar). we D.P. J. Biol. Chem. Full Text PDF PubMed Google Scholar) that hPR-A but not hPR-B, in the of either progesterone or transcriptional activity in and but not in the cell also of ER transcriptional activity when with a in MCF-7 breast cancer in the of D.P. Mol. Cell. Biol. PubMed Scopus Google Scholar). however, that hPR-B but not hPR-A of ER activity a complex region the when in MCF-7 J. Biol. Chem. Full Text PDF PubMed Google Scholar). These most from in the cell and contexts used for and in the of transcriptional and hPR-A also to function as a of other steroid hormone receptor activity O'Malley B.W. D.P. Mol. Endocrinol. 1993; 7: PubMed Scopus Google Scholar, D.P. J. Biol. Chem. Full Text PDF PubMed Google Scholar, D.P. Biol. Google however, the of these remains to be this inhibitory action of hPR-A to be to steroid hormone transcription as hPR-A is to D receptor activity and to heterologous activity and O'Malley B.W. D.P. Mol. Endocrinol. 1993; 7: PubMed Scopus Google Scholar). PR and ER are in the and of and are in the of of the breast 1990; 11: PubMed Scopus Google Scholar). In the of hPR-A, and hPR-B in these suggests that the of action of these receptors be is a to the mechanism of ER transcriptional activity. D.P. Mol. Cell. Biol. PubMed Scopus Google Scholar) that hPR-A the between progesterone and estrogen in progesterone and In of we that it is to ER transcriptional activity in MCF-7 by of hPR-A. In the PR is of as an of ER only in the of hPR-A. These of not the with and are mediated by a mechanism of action of is then that the of in the of and breast be a of to function as an as as an study the between hPR-A and hPR-B that to the A isoform the to transcriptional activity. it that the in the transcriptional of the two isoforms of the human to in hPR-B C.A. Mol. Endocrinol. PubMed Scopus Google Scholar). However, the that is also an activator of progesterone-responsive promoters but lacks the to that to hPR-A is for the in the transcriptional of the two human receptors. of the human and chicken that the proteins in that the difference between the human and the chicken A isoform of PR to the human A receptor the to steroid hormone receptor transcriptional activity. we show that only hPR-A but not hPR-B or is of transcriptional activity and that the N-terminal 140-amino acid region of hPR-A is for this repressor that the repressor region of hPR-A is but not for trans-repression of heterologous steroid receptor activity suggests that regions of the receptor other the of hPR-A are required for In of this it that the of hPR-A and region when in S. D.F. Edwards D.P. Mol. Endocrinol. 11: PubMed Scopus Google Scholar). Thus, it is that within the and the of hPR-B form a that the receptor to with required transcription this and that in this it that the to the activity of hPR-A and hPR-B is that both receptors for a of and that the complex with hPR-A is transcriptionally inactive but transcription by a transcription required by However, this is to be In we that the of hPR-A to transcriptional activity in a of the of the two receptors and the of hPR-A. This to a suggests that the inhibitory activity of hPR-A a the is that the between within the hPR-B region to with transcription factors within the cell which are from those that with hPR-A. we that in the of hormone hPR-B with the required for transcriptional activity. the other hPR-A with a of proteins and form a complex that with ligand-dependent transcriptional activity of all the steroid receptors. this only be the of the and the that the inhibitory activity of hPR-A in a this The progesterone receptor (PR) 1The abbreviations used are: PR, progesterone receptor; c, chicken; h, human; HSP, heat shock protein; PRE, progesterone response elements; DBD, DNA-binding domain; HBD, hormone-binding domain; GR, glucocorticoid receptor; ER, estrogen receptor; ERE, ER element; PCR, polymerase chain reaction; CMV, cytomegalovirus; BUS, B-upstream segment; 17β-E2, 17β-estradiol. 1The abbreviations used are: PR, progesterone receptor; c, chicken; h, human; HSP, heat shock protein; PRE, progesterone response elements; DBD, DNA-binding domain; HBD, hormone-binding domain; GR, glucocorticoid receptor; ER, estrogen receptor; ERE, ER element; PCR, polymerase chain reaction; CMV, cytomegalovirus; BUS, B-upstream segment; 17β-E2, 17β-estradiol. belongs to the superfamily of intracellular receptors that mediate the nuclear effects of steroid hormones, thyroid hormone, and the non-nutritional vitamins A and D (1Evans R.M. Science. 1988; 240: 889-895Crossref PubMed Scopus (6291) Google Scholar). The mechanism of action of PR is similar to that of the other steroid receptors. In the absence of ligand the receptor is transcriptionally inactive and remains sequestered in a large complex of heat shock proteins (HSPs) as follows: HSP-90, HSP-70, and P59 (2Smith D.F. Faber L.E. Toft D.O. J. Biol. Chem. 1990; 265: 3996-4003Abstract Full Text PDF PubMed Google Scholar, 3Bagchi M.K. Tsai S.-Y. Tsai M.-J. O'Malley B.W. Mol. Cell. Biol. 1991; 11: 4998-5004Crossref PubMed Scopus (50) Google Scholar, 4Pratt W.B. Hutchinson K.A. Scherrer L.W. Trends Endocrinol. Metab. 1992; 3: 326-333Abstract Full Text PDF PubMed Scopus (33) Google Scholar). Upon ligand binding, the receptor undergoes a distinct change in conformation (5DeMarzo A.M. Beck C.A. Onate S.A. Edwards D.P. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 72-76Crossref PubMed Scopus (106) Google Scholar) that results in the dissociation of a monomeric receptor from the heat shock complex (5DeMarzo A.M. Beck C.A. Onate S.A. Edwards D.P. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 72-76Crossref PubMed Scopus (106) Google Scholar, 6Renoir J.M. Radanyi C. Jung-Testas I. Faber L.E. Baulieu E.E. J. Biol. Chem. 1990; 265: 14402-14406Abstract Full Text PDF PubMed Google Scholar). Liganded receptors then spontaneously dimerize and bind to DNA via specific progesterone response elements (PREs) located within the regulatory regions of target genes (7Bagchi M.K. Elliston J.F. Tsai S.Y. Edwards D.P. Tsai M.-J. O'Malley B.W. Mol. Endocrinol. 1988; 2: 1221-1229Crossref PubMed Scopus (65) Google Scholar). The binding of either an agonist, or of most antagonists, converts the receptor into a DNA binding competent form (8Beekman J.M. Allan G.F. Tsai S.Y. Tsai M.-J. O'Malley B.W. Mol. Endocrinol. 1993; 7: 1266-1274PubMed Google Scholar). However, only agonist-bound PR receptors are of transcriptional when to The progesterone receptor is similar to that of other steroid receptors in that it a DNA-binding domain a hormone-binding domain the steroid receptors such as PR and glucocorticoid receptor and an N-terminal domain which is the most region the A. J. J. 1990; PubMed Scopus Google Scholar). The regions for receptor and with heat shock proteins are also located the within the of PR B.W. Mol. Endocrinol. 1990; PubMed Scopus Google Scholar). the also of the transcriptional domains J. 1992; 11: PubMed Scopus Google Scholar). The other transcriptional is located in the of the A. J. J. 1990; PubMed Scopus Google Scholar, C. J. Biol. Chem. 1992; Full Text PDF PubMed Google Scholar). The human PR is in that it as two isoforms hPR-B and hPR-A PubMed Scopus Google Scholar). The human is a form of hPR-B the first 164 N-terminal amino These two isoforms are transcribed from distinct estrogen-inducible promoters within a single copy PR A. U. J. 1990; PubMed Scopus Google Scholar). isoforms in most with the of the PR only as the isoform A. C. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). The of the two PR isoforms in forms similar DNA and ligand binding PubMed Scopus Google Scholar). However, progesterone-responsive transcription systems in that hPR-A and hPR-B are not A. J. J. 1990; PubMed Scopus Google Scholar, A. U. J. 1990; PubMed Scopus Google Scholar, O'Malley B.W. D.P. Mol. Endocrinol. 1993; 7: PubMed Scopus Google Scholar). hPR-B functions as a transcriptional activator in most contexts, whereas in most hPR-A not transcription but functions as a trans-dominant repressor of hPR-B, glucocorticoid receptor receptor, receptor, and estrogen receptor transcriptional activity O'Malley B.W. D.P. Mol. Endocrinol. 1993; 7: PubMed Scopus Google Scholar, D.P. J. Biol. Chem. Full Text PDF PubMed Google Scholar, D.P. Biol. Google Scholar). the human receptor, both the A and isoforms of the chicken PR as of progesterone-responsive genes in Toft D.O. O'Malley B.W. PubMed Scopus Google Scholar, 1988; PubMed Scopus Google Scholar, C. J. Mol. Biol. 1991; PubMed Scopus Google Scholar). Thus, although the of the and hPR-A are quite are quite different. A of the amino acid that and hPR-A are very most of the of the protein; however, are in we that the for the of and hPR-A within the that by and chimeras between the two proteins that the within hPR-A required for trans-repression be In this we show that the N-terminal 140-amino acid region of hPR-A is necessary, but not sufficient, for trans-repression of ER transcriptional activity. In that this repressor region of hPR-A requires other domains within the receptor to form the for is that this is required to a required for transcriptional activity. of progesterone to estrogen action in estrogen by ER the estrogen in 1990; 11: PubMed Scopus Google and ER action the The mechanism of progesterone action ER first in the These studies that ER of progesterone PubMed Scopus Google Scholar). it that ER in the of the be by J. Endocrinol. Metab. PubMed Scopus Google Scholar). studies in breast cancer Mol. Endocrinol. 3: PubMed Scopus Google Scholar, J. Mol. Endocrinol. 1990; PubMed Scopus Google Scholar) a in ER to ER a of of transcription of the ER progesterone is also of regulatory although the mechanism of this is not that PR ER transcriptional activity by a transcription for ER action D.P. J. Biol. Chem. Full Text PDF PubMed Google D.P. Mol. Cell. Biol. PubMed Scopus Google Scholar, Mol. Cell. Biol. PubMed Scopus Google Scholar, J. Biol. Chem. Full Text PDF PubMed Google Scholar). we D.P. J. Biol. Chem. Full Text PDF PubMed Google Scholar) that hPR-A but not hPR-B, in the of either progesterone or transcriptional activity in and but not in the cell also of ER transcriptional activity when with a in MCF-7 breast cancer in the of D.P. Mol. Cell. Biol. PubMed Scopus Google Scholar). however, that hPR-B but not hPR-A of ER activity a complex region the when in MCF-7 J. Biol. Chem. Full Text PDF PubMed Google Scholar). These most from in the cell and contexts used for and in the of transcriptional and hPR-A also to function as a of other steroid hormone receptor activity O'Malley B.W. D.P. Mol. Endocrinol. 1993; 7: PubMed Scopus Google Scholar, D.P. J. Biol. Chem. Full Text PDF PubMed Google Scholar, D.P. Biol. Google however, the of these remains to be this inhibitory action of hPR-A to be to steroid hormone transcription as hPR-A is to D receptor activity and to heterologous activity and O'Malley B.W. D.P. Mol. Endocrinol. 1993; 7: PubMed Scopus Google Scholar). PR and ER are in the and of and are in the of of the breast 1990; 11: PubMed Scopus Google Scholar). In the of hPR-A, and hPR-B in these suggests that the of action of these receptors be is a to the mechanism of ER transcriptional activity. D.P. Mol. Cell. Biol. PubMed Scopus Google Scholar) that hPR-A the between progesterone and estrogen in progesterone and In of we that it is to ER transcriptional activity in MCF-7 by of hPR-A. In the PR is of as an of ER only in the of hPR-A. These of not the with and are mediated by a mechanism of action of is then that the of in the of and breast be a of to function as an as as an study the between hPR-A and hPR-B that to the A isoform the to transcriptional activity. it that the in the transcriptional of the two isoforms of the human to in hPR-B C.A. Mol. Endocrinol. PubMed Scopus Google Scholar). However, the that is also an activator of progesterone-responsive promoters but lacks the to that to hPR-A is for the in the transcriptional of the two human receptors. of the human and chicken that the proteins in that the difference between the human and the chicken A isoform of PR to the human A receptor the to steroid hormone receptor transcriptional activity. we show that only hPR-A but not hPR-B or is of transcriptional activity and that the N-terminal 140-amino acid region of hPR-A is for this repressor that the repressor region of hPR-A is but not for trans-repression of heterologous steroid receptor activity suggests that regions of the receptor other the of hPR-A are required for In of this it that the of hPR-A and region when in S. D.F. Edwards D.P. Mol. Endocrinol. 11: PubMed Scopus Google Scholar). Thus, it is that within the and the of hPR-B form a that the receptor to with required transcription this and that in this it that the to the activity of hPR-A and hPR-B is that both receptors for a of and that the complex with hPR-A is transcriptionally inactive but transcription by a transcription required by However, this is to be In we that the of hPR-A to transcriptional activity in a of the of the two receptors and the of hPR-A. This to a suggests that the inhibitory activity of hPR-A a the is that the between within the hPR-B region to with transcription factors within the cell which are from those that with hPR-A. we that in the of hormone hPR-B with the required for transcriptional activity. the other hPR-A with a of proteins and form a complex that with ligand-dependent transcriptional activity of all the steroid receptors. this only be the of the and the that the inhibitory activity of hPR-A in a this The of progesterone to estrogen action in estrogen by ER the estrogen in 1990; 11: PubMed Scopus Google and ER action the The mechanism of progesterone action ER first in the These studies that ER of progesterone PubMed Scopus Google Scholar). it that ER in the of the be by J. Endocrinol. Metab. PubMed Scopus Google Scholar). studies in breast cancer Mol. Endocrinol. 3: PubMed Scopus Google Scholar, J. Mol. Endocrinol. 1990; PubMed Scopus Google Scholar) a in ER to ER a of of transcription of the ER Interestingly, progesterone is also of regulatory although the mechanism of this is not that PR ER transcriptional activity by a transcription for ER action D.P. J. Biol. Chem. Full Text PDF PubMed Google D.P. Mol. Cell. Biol. PubMed Scopus Google Scholar, Mol. Cell. Biol. PubMed Scopus Google Scholar, J. Biol. Chem. Full Text PDF PubMed Google Scholar). we D.P. J. Biol. Chem. Full Text PDF PubMed Google Scholar) that hPR-A but not hPR-B, in the of either progesterone or transcriptional activity in and but not in the cell also of ER transcriptional activity when with a in MCF-7 breast cancer in the of D.P. Mol. Cell. Biol. PubMed Scopus Google Scholar). however, that hPR-B but not hPR-A of ER activity a complex region the when in MCF-7 J. Biol. Chem. Full Text PDF PubMed Google Scholar). These most from in the cell and contexts used for and in the of transcriptional and Interestingly, hPR-A also to function as a of other steroid hormone receptor activity O'Malley B.W. D.P. Mol. Endocrinol. 1993; 7: PubMed Scopus Google Scholar, D.P. J. Biol. Chem. Full Text PDF PubMed Google Scholar, D.P. Biol. Google however, the of these remains to be this inhibitory action of hPR-A to be to steroid hormone transcription as hPR-A is to D receptor activity and to heterologous activity and O'Malley B.W. D.P. Mol. Endocrinol. 1993; 7: PubMed Scopus Google Scholar). PR and ER are in the and of and are in the of of the breast 1990; 11: PubMed Scopus Google Scholar). In the of hPR-A, and hPR-B in these suggests that the of action of these receptors be is a to the mechanism of ER transcriptional activity. D.P. Mol. Cell. Biol. PubMed Scopus Google Scholar) that hPR-A the between progesterone and estrogen in progesterone and In of we that it is to ER transcriptional activity in MCF-7 by of hPR-A. In the PR is of as an of ER only in the of hPR-A. These of not the with and are mediated by a mechanism of action of is then that the of in the of and breast be a of to function as an as as an This study the between hPR-A and hPR-B that to the A isoform the to transcriptional activity. it that the in the transcriptional of the two isoforms of the human to in hPR-B C.A. Mol. Endocrinol. PubMed Scopus Google Scholar). However, the that is also an activator of progesterone-responsive promoters but lacks the to that to hPR-A is for the in the transcriptional of the two human receptors. of the human and chicken that the proteins in that the difference between the human and the chicken A isoform of PR to the human A receptor the to steroid hormone receptor transcriptional activity. we show that only hPR-A but not hPR-B or is of transcriptional activity and that the N-terminal 140-amino acid region of hPR-A is for this repressor activity. that the repressor region of hPR-A is but not for trans-repression of heterologous steroid receptor activity suggests that regions of the receptor other the of hPR-A are required for In of this it that the of hPR-A and region when in S. D.F. Edwards D.P. Mol. Endocrinol. 11: PubMed Scopus Google Scholar). Thus, it is that within the and the of hPR-B form a that the receptor to with required transcription this and that in this it that the to the activity of hPR-A and hPR-B is that both receptors for a of and that the complex with hPR-A is transcriptionally inactive but transcription by a transcription required by However, this is to be In we that the of hPR-A to transcriptional activity in a of the of the two receptors and the of hPR-A. This to a suggests that the inhibitory activity of hPR-A a the is that the between within the hPR-B region to with transcription factors within the cell which are from those that with hPR-A. we that in the of hormone hPR-B with the required for transcriptional activity. the other hPR-A with a of proteins and form a complex that with ligand-dependent transcriptional activity of all the steroid receptors. this only be the of the and the that the inhibitory activity of hPR-A in a this of and for and the of this