Identification of a group of Ser-Pro motif hormone-inducible phosphorylation sites in the human progesterone receptor.

Zhang, Yixian; Beck, Candace A.; Poletti, A.; Edwards, Dean P.; Weigel, Nancy L.

doi:10.1210/mend.9.8.7476977

Cited by 39 publications

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“…Sites of phosphorylation have been identified for certain members of the steroid/thyroid receptor family including mouse glucocorticoid receptor (8), chicken (9,10) and human progesterone receptor (PR) 1 (11,12), human estrogen receptor (13)(14)(15), androgen receptor (16), and the vitamin D receptor (17). The major targets for phosphorylation are serine residues located in the N-terminal domain that is required for maximal transcriptional activity.…”

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confidence: 99%

“…Phosphorylation of human PR is complex. PR-B has at least nine phosphoserines N-terminal to the DNA binding region (3,11,12). Three sites identified as Ser 81 , Ser…”

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confidence: 99%

“…, and Ser 162 (11,12) are contained in the unique N-terminal segment of PR-B; the remaining sites are common to PR-A and PR-B. There appears to be two classes of phosphorylation sites based on how they are affected by progestin agonists.…”

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confidence: 99%

“…Three sites found in Ser-Pro consensus sequences, Ser 102 , Ser 294 , and Ser 345 , are highly inducible and were detected as major new sites only after treatment of cells with hormone agonist. The remaining sites are basally phosphorylated in the absence of hormone and exhibit a general increase in response to hormone agonist (12). Additionally, progestin agonists such as R5020 cause human PR to exhibit a slightly slower electrophoretic mobility on SDSgels which is associated with phosphorylation of a single site at Ser 345 (12).…”

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confidence: 99%

“…The remaining sites are basally phosphorylated in the absence of hormone and exhibit a general increase in response to hormone agonist (12). Additionally, progestin agonists such as R5020 cause human PR to exhibit a slightly slower electrophoretic mobility on SDSgels which is associated with phosphorylation of a single site at Ser 345 (12). Steroid analogs have been developed that function as potent competitive antagonists of progesterone (22).…”

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confidence: 99%

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Two Types of Anti-progestins Have Distinct Effects on Site-specific Phosphorylation of Human Progesterone Receptor

Beck

Zhang

Weigel

et al. 1996

Journal of Biological Chemistry

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, and Ser 345) are inducible by hormone agonist, while at least six others are basally phosphorylated and exhibit a general increase in response to hormone. In this study we have used high performance liquid chromatography phosphopeptide mapping and manual peptide sequencing to investigate how two different progestin antagonists, RU486 and ZK98299, affect site-specific phosphorylation of PR isolated from T47D breast cancer cells. As compared to the progestin agonist R5020, RU486 stimulated a similar increase in overall incorporation of [ 32 P]phosphate per PR molecule (2.5-2.6-fold for PR-A and 2.1-fold for PR-B), and at the site-specific level, RU486 stimulated both the basal and inducible sites to the same extent as R5020. In contrast, ZK98299 produced only a minimal increase in overall phosphorylation (1.2-fold for PR-A and 1.1-fold for PR-B) which was due to a reduced stimulation of the basal sites and failure to induce any of the three hormone-dependent sites. No inappropriate phosphorylation sites were detected in response to either RU486 or ZK98299. In cotreatment studies, ZK98299 blocked the increase in overall phosphorylation of PR induced by R5020, demonstrating that the failure of this antagonist to stimulate specific phosphorylation sites is not due to an inefficient interaction with PR in the intact cell. These results indicate that the biological effects of RU486 are not mediated by an alteration in the phosphorylation state of PR, whereas failure to promote phosphorylation of certain sites may contribute to the antagonist action of ZK98299. Additionally these results support the concept of two mechanistic classes of anti-progestins that affect PR differently in vivo.

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confidence: 99%

“…Phosphorylation of human PR is complex. PR-B has at least nine phosphoserines N-terminal to the DNA binding region (3,11,12). Three sites identified as Ser 81 , Ser…”

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Two Types of Anti-progestins Have Distinct Effects on Site-specific Phosphorylation of Human Progesterone Receptor

Beck

Zhang

Weigel

et al. 1996

Journal of Biological Chemistry

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Ligand-independent activation of steroid hormone receptors

Weigel

Zhang

1998

Journal of Molecular Medicine

310

159

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In addition to the conventional hormone-dependent regulation of the activity of steroid/thyroid receptor family members, many studies have shown that there is substantial cross-talk between signal transduction pathways and steroid receptors. In a number of cases the modulation of kinase/phosphatase activity in cells leads to activation of steroid receptors in the absence of hormone. This novel mechanism may not be ubiquitous as the glucocorticoid receptor appears to be refractory to activation in the absence of hormone. However, estrogen receptors, progesterone receptors, androgen receptors, retinoic acid receptors, retinoid X receptors, and vitamin D receptors all exhibit ligand-independent activation under appropriate conditions. Whether a steroid receptor responds to a signal by inducing transcription of a target gene in the absence of hormone depends upon the cell type, promoter, and activator. The mechanism(s) by which ligand-independent activation is induced is currently a subject of great interest. Because the signals that activate receptors induce protein phosphorylation, altered phosphorylation of the receptors, and/or proteins that associate with the receptors are likely to be key to ligand-independent activation. In the case of the estrogen receptor there is good evidence that altered receptor phosphorylation plays a role in ligand-independent activation. Other likely targets are proteins in the heat shock protein complexes, corepressors, and/or coactivators of steroid receptors.

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Recent developments in molecular action of antihormones

Fuhrmann¹,

Parczyk²,

Klotzbücher³

et al. 1998

Journal of Molecular Medicine

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Antihormones are by definition antagonists of steroid hormone action. They interact with the ligand binding domains of steroid hormone receptors and competitively inhibit the action of the receptors by mechanisms that are not quite understood. In certain cases antihormones also exhibit agonistic activity especially in connection with certain naturally occurring receptor mutants. These observations together with findings of indiscriminate interaction of antihormones with several classes of steroid receptors have necessitated a search of more effective and reliable antihormones. Recent advances in the resolution of the crystal structure of the ligand binding domains of certain members of the steroid receptor family and identification of non-liganded activation of steroid receptors have produced considerable information that can be harnessed into a fruitful search for a new generation of antihormones.

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Identification of a group of Ser-Pro motif hormone-inducible phosphorylation sites in the human progesterone receptor.

Cited by 39 publications

References 0 publications

Two Types of Anti-progestins Have Distinct Effects on Site-specific Phosphorylation of Human Progesterone Receptor

Two Types of Anti-progestins Have Distinct Effects on Site-specific Phosphorylation of Human Progesterone Receptor

Ligand-independent activation of steroid hormone receptors

Recent developments in molecular action of antihormones

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