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In contrast to progestin-induced Ser phosphorylation, which occurs within 30—60 min independently of MAPK activation, growth factor-induced Ser phosphorylation occurs within 3—5 min and is MAPK dependent Ser phosphorylation is required to sustain transcriptional synergy in the presence of progestins and growth factors 22 , and to signal for ligand-induced receptor down-regulation by the ubiquitin-proteasome pathway After ligand binding, PR undergo rapid down-regulation This process is dependent on phosphorylation of Ser, which targets liganded PR for ubiquitination and degradation by the 26S-proteosome pathway Mutant PR, in which Ser has been replaced by alanine SA , binds ligand and like wild-type wt PR, undergoes a characteristic upshift in gel mobility due to phosphorylation at other sites , enters the nucleus, and binds to PRE elements 21 — 23 , However, it fails to be ubiquitinated and is thus highly stable in the presence of progestins relative to wt PR Interestingly, liganded mutant SA PR is a weak transcriptional activator when stably expressed in breast cancer cells, and does not undergo synergistic regulation in response to agents that activate MAPK Thus, phosphorylation of PR Ser couples increased transcriptional activity to rapid down-regulation of PR protein by the ubiquitin-proteosome pathway.

Indeed, the classic view of proteasome-mediated protein down-regulation predicts that ubiquitination serves to tag regulatory proteins for destruction by the multisubunit proteasome complex to rapidly attenuate the signal. Salghetti et al.

References

Furthermore, a close correlation exists between the ability of an acidic activation domain to both activate transcription and signal proteolysis. Phosphorylation is a prerequisite for degron function of the yeast cyclins, Cln2 36 and Cln3 These elements activated transcription when fused to a DNA-binding domain Thus, short-lived transcription factors may be rapidly destroyed because of their ability to efficiently activate transcription, perhaps through a common cellular machinery triggered by phosphorylation events.

In support of this idea, the ubiquitin-protein ligases, hRPF1 38 and E6-AP 39 , have been shown to function as coactivators for liganded steroid hormone receptors, including PR. The Met30 ubiquitin-ligase is required for the transcriptional activity of the VP16 transcriptional activation domain; fusion of ubiquitin to the VP16 activator bypassed this requirement, indicating that ubiquitination is essential for transcriptional activation Phosphorylation of Ser may also mediate some aspects of ligand-independent PR action.

Thus, the nuclear localization of the PR is regulated by multiple mechanisms; progestin-induced translocation is independent of Ser phosphorylation and MAPKs. Ligand-independent PR effects in neuroendocrine cells have been shown to mediate sexual behavior in rodents in response to dopamine 42 , 43 ; dopaminergic ligand-independent action of chick PR maps to a required serine residue Additionally, Labriola et al.

Qiu et al. These events required ligand binding, but were greatly augmented by MAPK activation 22 , The reasons for these differences are unknown, but may involve differential expression of EGF receptor family members expressed on the cell surface between T47D cell line clones, leading to differences in the activation of downstream intracellular kinases.

In any case, these exciting data 23 , 26 suggest that regulation of the PR by alternate signaling pathways, including the elevated MAPK activity, often exhibited by breast tumors, is likely to contribute to disregulated gene expression and changes in cell growth. In contrast to Ser, Ser of human PR is both basally phosphorylated and regulated by ligand in vivo , and Ser phosphorylation has been demonstrated to be mediated by CDK2 in vitro Like mitogens, progestins regulate CDK2 activity 8 , Similarly, recent evidence suggests that, in addition to progestins, mitogenic stimuli also induce rapid and robust phosphorylation of PR Ser However, this event suggests a mechanism of cell cycle-dependent regulation of PR.

In contrast to Ser, phospho-Ser PRs undergo delayed ligand-induced down-regulation relative to PRs that are not phosphorylated on Ser, suggesting that phosphorylation of Ser may stabilize PR protein In addition, CDK2 overexpression increased PR transcriptional activity in the presence or absence of ligand. Mutation of Ser to alanine selectively blocked the increase in PR transcriptional activity observed in the absence of ligand but had little effect on that induced by progestin binding Interestingly, Ser is adjacent to a nine-amino acid destruction D -box motif, indicating that alteration of PR turnover may be a primary means by which PR transcriptional activities are regulated in response to phosphorylation Similar to human PR, the phosphorylation status of mouse GR has a profound effect on the stability of the receptor protein: GR containing seven or eight mutated serine-phospho sites have a markedly extended half-life and do not show the ligand-dependent destabilization seen with wt receptor However, in contrast to PR, the transcriptional activity of human GR was enhanced by proteasome inhibition, and mutation of Lys within an N-terminal proline, glutamic acid, serine, and threonine PEST element both abrogated ligand-dependent down-regulation of GR protein and simultaneously enhanced GR-induced transcriptional activity In contrast to the classically defined function of PRs as ligand-activated nuclear transcription factors, studies of amphibian oocyte maturation make it clear that PRs can also mediate the activation of cytoplasmic signaling pathways.

Progesterone induces germinal vesicle breakdown and activation of phospholipases C and the cell cycle kinase Cdc2 in enucleated amphibian eggs 55 — These effects appear to be mediated through a cytosolic PR that has transcriptional activity, although transcription is not required for germinal vesicle breakdown 60 , This results in the activation of the cyclin B-Cdc-2 complex, which catalyzes entry into M phase of meiosis I reviewed in Ref. Expression of exogenous constitutively active MEK causes oocyte maturation in the absence of progesterone, and antibodies that bind MEK block progesterone-mediated maturation 62 , Amphibian PR has also been shown to physically associate with cytosolic kinases, including p42 MAPK and phosphatidylinositol-3 kinase These data suggest that in nonmammalian systems, PR is able to regulate cell cycle progression by kinase signaling independently of its transcriptional activity.

Interestingly, a novel membrane progesterone receptor mPR gene was recently cloned from spotted sea trout ovaries, and structural analyses indicates that it encodes a seven transmembrane-spanning G protein-coupled receptor The mPR in fish oocytes was up-regulated in response to progestin treatment, suggesting a role for nuclear PR in this process The relative contributions of nuclear PR vs. PR can also function as a signaling molecule independently of its transcriptional activity in mammalian systems Fig. Indeed, the extranuclear actions of steroid hormone receptors have become an intense area of investigation, particularly in breast cancer cell models 67 — Migliaccio et al.

Progestin treatment of breast cancer cells causes a rapid and transient activation of MAPK signaling that is PR dependent but independent of PR transcriptional activity 71 , Whereas the genomic effects of progestin treatment are latent i. Human PR contains a proline-rich PXXP motif that mediates direct binding to the Src homology 3 SH3 domains of signaling molecules in the pSrc kinase family in a ligand-dependent manner A polyproline-rich sequence in the androgen receptor interacts with c-Src by a similar mechanism Phosphorylated PR may recruit regulatory molecules that function in one or more of these interconnected processes, perhaps linked by a common cellular machinery.

PR and growth factors activate MAPKs independently, and this may result in positive regulation of PR action via feed-back regulation i.

Hormone receptor

Ballare et al. In contrast to the studies conducted by Boonyaratanakornkit et al. However, Boonyaratanakornkit et al. Although the reasons for these discrepancies must be resolved, it is possible that overexpression of steroid receptors in COS-7 cells leads to concentration-dependent effects resulting in the formation of subtly different signaling complexes that depend on the presence of other signaling and adaptor molecules. In support of this idea, Wong et al. Taken together, these data indicate that multiple and complex interactions contribute to direct protein kinase activation by steroid hormone receptors and suggest that at least some of the nongenomic signaling functions of amphibian PR have been conserved in mammals.

A role for a separate gene product encoding the putative mammalian homolog of mPR 76 remains to be determined. The physiological role s of steroid hormone receptor-mediated activation of cytoplasmic signaling molecules is not yet clear in mammalian systems but could theoretically serve to potentiate several functions of PR Fig. One prospective role of this cytoplasmic activation is to provide a mechanism for rapid, direct phosphorylation of PR coincident with ligand binding, thus allowing a form of PR-induced amplification of the signal or positive feedback.

This feedback has a dramatic influence on PR function Fig. In support of this idea, microinjection of breast cancer cell lines with cDNA of catalytically inactive c-Src or anti-Ras antibodies blocked estradiol and progestin-dependent cell cycle progression The role of cytoplasmic signaling cascades and estrogen action has been expertly reviewed 81 — In addition to the direct regulation of gene transcription by PR i.

ETS proteins promote G 1 phase progression by the regulation of a number of genes involved in control of cell proliferation, including the cell cycle regulator cyclin D1 Cyclin D1 activates and defines the substrate specificity of CDKs 4 and 6, whose activity is required for progression from G 1 to S phase 85 , CDKs are inactive in the absence of cyclins; thus the availability or abundance of cyclin D1 is a major determinant for cell cycle progression through G 1 Interestingly, cyclin D1 null mice exhibit deficiencies in mammary gland development, including specific defects in alveolar growth 90 , 91 , a phenotype similar to that exhibited in adult female mice lacking PR 92 , Recently, the oncogenic effects of cyclin D1 overexpression were found to be mediated by a novel interaction with the transcription factor CCAAT enhancer binding protein The cyclin D1 promoter is complex, containing multiple target elements for transcription factors inputs, but lacks a canonical PRE.

Cyclin D1 protein levels, however, do increase in response to progestin treatment alone 8 and are synergistically regulated by progestins and growth factors in a MAPK-dependent manner 32 , 77 , a phenomenon that may partially explain the mitogenic actions of progestins. Lange, unpublished results. Thus, the activation of cytoplasmic signaling pathways by liganded PR provides both enhanced PR action at specific PR-regulated genes 9 , 22 and couples this to the regulation of additional growth-regulatory genes, the promoters of which function independently of PR but utilize PR-activated MAPK pathways Fig.

Rather than acting in an obligatory or switch-like manner, phosphorylation is generally thought to exert subtle effects on nuclear steroid hormone receptors. However, one caveat of this conclusion is that it is based largely on observations made with liganded receptors in the absence of controlled activation of alternate signaling pathways. Transcriptional readouts have focused primarily on steroid receptor function at cognate response elements as part of artificial promoter-reporter gene contexts in which maximal reactions are driven.

EXPERIMENTAL PROCEDURES

Indeed, studies with human PR reviewed herein suggest that the effects of phosphorylation are somewhat more profound in the context of multiple signaling inputs. Perhaps a more accurate conclusion is that the phosphorylation status of a particular steroid hormone receptor serves as a direct sensor to cellular kinase activities to coordinate responses to growth factors and steroid hormones.

Mechanism of STEROID HORMONE action

In the absence of alternate stimuli, independent activation of MAPKs by extranuclear liganded steroid hormone receptors may result in positive regulation of receptor action via feed-back regulation by direct phosphorylation. Theoretically, this may occur in both the presence and absence of steroid hormone ligands and on diverse gene promoters.


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In addition, activation of cytoplasmic kinase cascades including MAPK modules by liganded receptors provides for regulation of gene targets the promoters of which are entirely independent of steroid receptor transcriptional activities, but rely on the activity of classical MAPK-targeted transcription factors such as the Ets family members, Elk-1, c-myc, fos, and jun.

This important linkage provides for well-integrated control of a large number of genes or gene subsets coordinately regulated in response to convergence of growth factor and steroid hormone receptor signaling. Finally, the newly discovered ability of steroid receptors to activate kinase pathways classically defined as key regulators of cell growth is likely to play an important role in the development of resistance to endocrine therapies Oxford University Press is a department of the University of Oxford.

It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Advanced Search. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents. Oxford Academic. Google Scholar. Cite Citation. Permissions Icon Permissions. Abstract In classical models of nuclear steroid hormone receptor function, ligand binds receptor, heat shock proteins dissociate, and receptor dimers enter or are withheld in the nucleus and interact with coregulatory molecules to mediate changes in gene expression.

Steroid Hormone Receptor Systems by W. W. Leavitt - speechyluncalsupp.ml

Open in new tab Download slide. Search ADS. The hspbased chaperone system: involvement in signal transduction from a variety of hormone and growth factor receptors. Fatty acid synthetase and its mRNA are induced by progestins in breast cancer cells. Co-operation of progestational steroids with epidermal growth factor in activation of gene expression in mammary tumor cells. Biphasic regulation of breast cancer cell growth by progesterone: role of the cyclin-dependent kinase inhibitors, p21 and p27 Kip1. Because of the relatively large size of enzymes and receptors, the large amount of surface area provides the basis for these weak interactions to occur.

This binding is actually highly specific because of the complementarity of these interactions between polar, non-polar, charged, neutral, hydrophilic, or hydrophobic residues. Upon binding, the receptor often undergoes a conformational change and may bind further, signaling ligands to activate a signaling pathway. Because of these highly specific and high affinity interactions between hormones and their receptors, very low concentrations of hormone can produce significant cellular response.

Therefore, hormone binding to its receptor is a complex process that can be mediated by cooperative binding, reversible and irreversible interactions, and multiple binding sites. The presence of hormone or multiple hormones enables a response in the receptor, which begins a cascade of signaling. The hormone receptor interacts with different molecules to induce a variety of changes, such as an increase or decrease of nutrient sources, growth, and other metabolic functions. These signaling pathways are complex mechanisms mediated by feedback loops where different signals activate and inhibit other signals.

If a signaling pathway ends with the increase in production of a nutrient, that nutrient is then a signal back to the receptor that acts as a competitive inhibitor to prevent further production.


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