1,721,066 research outputs found
Signaling functions of ubiquitin in the 17β-estradiol (E2):estrogen receptor (ER) α network
No full textProtein posttranslational modifications (PTMs) are signaling alterations that allow coordinating the cellular responses with the changes in the extracellular environment. In this way, the posttranslationally-modified protein becomes a switch node in the transduction network activated by the specific extracellular stimuli. It is now clear that this is the case also for protein ubiquitination: this extremely versatile PTM controls cell physiology through the modulation of protein stability as well as through the modulation of the dynamics of the intracellular signaling cascades. Recent evidence clearly indicates that such a complex scheme appears to be valid also for the 17β-estradiol (E2):estrogen receptor (ER) α signal transduction pathways. Indeed, beside the long standing notion that ERα ubiquitination is required for the regulation of receptor stability, several laboratories, including our own, have clearly indicated that ERα ubiquitination also serves non-degradative functions. This review will reconsider the role of ubiquitination in E2:ERα signaling by particularly highlighting how the functions of the non-degradative ubiquitination impact on ERα activities and contribute to the modulation of E2-dependent physiological processes
Modulation of estrogen receptor a levels by endogenous and exogenous ligands
No full textERα is a ligand-activated transcription factor, member of the nuclear receptor superfamily. Regulation of ERa levels is intrinsically required for its transcriptional activity and thus for the modulation of the physiological actions of the cognate hormone 17β-estradiol (E2). Indeed, ERa exogenous ligands that target this molecular circuitry are used as drugs in clinical practice. Interestingly, some natural and synthetic molecules, which human beings are commonly exposed to, interfere with the endocrine system and operate through ERα by selectively modifying its signalling. In addition, these molecules may also modulate ERa cellular content. Here, we report the recent advances in our understanding of how exogenous ERα ligands impact on receptor levels and change the physiological El-dipendent modulation of specific cellular function
Identification of an estrogen receptor alpha non-covalent ubiquitin binding surface: role in 17beta-estradiol-induced transcriptional activity
No full text""Ubiquitin (Ub)-binding domains (UBDs) located in Ub receptors decode the ubiquitination signal by non-covalently engaging the Ub modification on their binding partners and transduce the Ub signalling through Ub-based molecular interactions. In this way, inducible protein ubiquitination regulates diverse biological processes. The estrogen receptor alpha (ERα) is a ligand-activated transcription factor that mediates the pleiotropic effects of the sex hormone 17β-estradiol (E2). Fine regulation of E2 pleiotropic actions depends on E2-dependent ERα association with a plethora of binding partners and\\\/or on the E2 modulation of receptor ubiquitination. Indeed, E2-induced ERα polyubiquitination triggers receptor degradation and transcriptional activity, and E2-dependent reduction in ERα monoubiquitination is crucial for E2 signalling. Monoubiquitinated proteins often contain UBDs, but whether non-covalent Ub-ERα binding could occur and play a role in E2-ERα signalling is unknown. Here, we report an Ub-binding surface within the ERα ligand binding domain that directs in vitro the receptor interaction with both ubiquitinated proteins and recombinant Ub chains. Mutational analysis reveals that ERα residues leucine 429 and alanine 430 are involved in Ub binding. Moreover, impairment of ERα association to ubiquitinated species strongly affects E2-induced ERα transcriptional activity. Considering the importance of UBDs in the Ub-based signalling network and the central role of different ERα binding partners in the modulation of E2-dependent effects, our discoveries provide novel insights into ERα activity that could also be relevant for ERα-dependent diseases."
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
17β-Estradiol-induced cell proliferation requires estrogen receptor (ER) α monoubiquitination
No full textProtein monoubiquitination (monoUbq) (i.e., the attachment of one single ubiquitin to the substrate) is a non-proteolytic reversible modification that controls protein functions. Among other proteins, the estrogen receptor α (ERα), which mediates the pleiotropic effects of the cognate hormone 17β-estradiol (E2), is a monoubiquitinated protein. Although it has been demonstrated that E2 rapidly reduces ERα monoUbq in breast cancer cells, the impact of monoUbq in the regulation of the ERα activities is poorly appreciated. Here, we show that mutation of the ERα monoUbq sites prevents the E2-induced ERα phosphorylation in the serine residue 118 (S118), reduces ERα transcriptional activity, and precludes the ERα-mediated extranuclear activation of signaling pathways (i.e., AKT activation) thus impeding the E2-induced cyclin D1 promoter activation and consequently cell proliferation. In addition, the interference with ERα monoUbq deregulates E2-induced association of ERα to the insulin like growth factor receptor (IGF-1-R). Altogether these data demonstrate an inherent role for monoUbq in ERα signaling and point to the physiological function of ERα monoUbq in the regulation of E2-induced cell proliferation
Susceptibility of estrogen receptor rapid responses to xenoestrogens: Physiological outcomes
No full text""17β-Estradiol (E2) binding induces rapid modification in the conformation of its cognate receptors (i.e., ERα and ERβ). These allosteric changes allow the association of ERs with cell specific transcriptional cofactors, thus determining cellular contexts specific variations in gene expression. In addition, E2-ER complexes could also interact with membrane and cytosolic signal molecules triggering extra-nuclear signalling pathways. The synergy between these mechanisms is necessary for E2-induced pleiotropic actions in target tissues. Besides E2, the ER ligand binding domains can accommodate many other natural and synthetic ligands. Several of these compounds act as agonist or antagonist of ER transcriptional activity due to their ability to modify the interactions between ERs and transcriptional co-regulators. However, the ability of natural or manmade ER ligands to affect the extra-nuclear interactions of the ERs has been rarely evaluated. Here, the ability of two diet-derived flavonoids (i.e., naringenin and quercetin) and of the synthetic food-contaminant bisphenol A to modulate specifically ER extra-nuclear signalling pathways will be reported. All the tested compounds bind to both ER subtypes even if lesser than E2 activating divergent signal transduction pathways. In fact, in the presence of ERα, both naringenin and quercetin decouple ERα activities by specifically interfering with ERα membrane initiating signals. On the other hand, bisphenol A, but not flavonoids, maintains ERβ at the membrane thus impairing the activation of the downstream kinases. As a whole, extra-nuclear ER signals are highly susceptible to different ligands that, by unbalancing E2-induced cell functions drive cells to different functional endpoints.. . "
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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