RESUMEN
Alterations in estrogen-mediated cellular signaling have largely been implicated in the pathogenesis of breast cancer. Here, we investigated the signaling regulation of a splice variant of the estrogen receptor, namely estrogen receptor (ERα-36), associated with a poor prognosis in breast cancers. Coupling in vitro and in vivo approaches we determined the precise sequential molecular events of a new estrogen signaling network in an ERα-negative cell line and in an original patient-derived xenograft. After estrogen treatment, ERα-36 rapidly associates with Src at the level of the plasma membrane, initiating downstream cascades, including MEK1/ERK activation and paxillin phosphorylation on S126, which in turn triggers a higher expression of cyclin D1. Of note, the direct binding of ERα-36 to ERK2 prevents its dephosphorylation by MKP3 and enhances the downstream signaling. These findings improve our understanding of the regulation of non-genomic estrogen signaling and open new avenues for personalized therapeutic approaches targeting Src or MEK in ERα-36-positive patients.
Asunto(s)
Neoplasias de la Mama/genética , Receptor alfa de Estrógeno/genética , MAP Quinasa Quinasa 1/genética , Proteína Oncogénica pp60(v-src)/genética , Isoformas de Proteínas/genética , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Receptor alfa de Estrógeno/biosíntesis , Femenino , Humanos , Células MCF-7 , Ratones , Isoformas de Proteínas/biosíntesis , Transducción de Señal , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The mechanism of the alkaline hydrolysis of phosphate and sulfate esters is of great interest. Ab initio quantum mechanical calculations and dielectric continuum methods are used to investigate the effect of the solvent on the associative/dissociative and the in-line/sideways character of the hydrolysis reaction of ethylene sulfate (ES) and ethylene phosphate (EP(-)), and their acyclic counterparts, dimethyl sulfate (DMS) and dimethyl phosphate (DMP(-)). The gas-phase reaction coordinates are determined by Hartree-Fock and density functional theory. For ES, the reaction coordinate in solution is determined; for the other three reactions only the transition state in solution is obtained. The alterations in the reaction induced by solvent are interpreted by use of the Hammond and anti-Hammond postulates.
Asunto(s)
Organofosfatos/química , Sulfatos/química , Etilenos/química , Hidrólisis , Modelos Moleculares , Compuestos Organofosforados/química , Soluciones , Ésteres del Ácido Sulfúrico/química , TermodinámicaRESUMEN
omega-Conotoxin MVIIA is a 25-residue, disulfide-bridged polypeptide from the venom of the sea snail Conus magus that binds to neuronal N-type calcium channels. It forms a compact folded structure, presenting a loop between Cys8 and Cys15 that contains a set of residues critical for its binding. The loop does not have a unique defined structure, nor is it intrinsically flexible. Broadening of a subset of resonances in the NMR spectrum at low temperature, anomalous temperature dependence of the chemical shifts of some resonances, and exchange contributions to J(0) from (13)C relaxation measurements reveal that conformational exchange affects the residues in this loop. The effects of this exchange on the calculated structure of omega-conotoxin MVIIA are discussed. The exchange appears to be associated with a change in the conformation of the disulfide bridge Cys8-Cys20. The implications for the use of the omega-conotoxins as a scaffold for carrying other functions is discussed.
Asunto(s)
Conformación Proteica , omega-Conotoxinas/química , Animales , Espectroscopía de Resonancia Magnética , CaracolesRESUMEN
Since september 1989, 3 psychiatric nurses have been working with the crisis and psychiatric emergencies unit of the emergency service of Saint-Luc Hospital in Brussels (Belgium). In this paper, the authors examine the specific functions of psychiatric nurses in the taking in charge of psychiatric emergencies and functional somatic complaints, as well as their role in relation with the nursing team as a whole.