Dataset Information

Lysosomal function is involved in 17?-estradiol-induced estrogen receptor ? degradation and cell proliferation.

ABSTRACT: The homeostatic control of the cellular proteome steady-state is dependent either on the 26S proteasome activity or on the lysosome function. The sex hormone 17?-estradiol (E2) controls a plethora of biological functions by binding to the estrogen receptor ? (ER?), which is both a nuclear ligand-activated transcription factor and also an extrinsic plasma membrane receptor. Regulation of E2-induced physiological functions (e.g., cell proliferation) requires the synergistic activation of both transcription of estrogen responsive element (ERE)-containing genes and rapid extra-nuclear phosphorylation of many different signalling kinases (e.g., ERK/MAPK; PI3K/AKT). Although E2 controls ER? intracellular content and activity via the 26S proteasome-mediated degradation, biochemical and microscopy-based evidence suggests a possible cross-talk among lysosomes and ER? activities. Here, we studied the putative localization of endogenous ER? to lysosomes and the role played by lysosomal function in ER? signalling. By using confocal microscopy and biochemical assays, we report that ER? localizes to lysosomes and to endosomes in an E2-dependent manner. Moreover, the inhibition of lysosomal function obtained by chloroquine demonstrates that, in addition to 26S proteasome-mediated receptor elimination, lysosome-based degradation also contributes to the E2-dependent ER? breakdown. Remarkably, the lysosome function is further involved in those ER? activities required for E2-dependent cell proliferation while it is dispensable for ER?-mediated ERE-containing gene transcription. Our discoveries reveal a novel lysosome-dependent degradation pathway for ER? and show a novel biological mechanism by which E2 regulates ER? cellular content and, as a consequence, cellular functions.

SUBMITTER: Totta P

PROVIDER: S-EPMC3988130 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Lysosomal function is involved in 17β-estradiol-induced estrogen receptor α degradation and cell proliferation.

Totta Pierangela P Pesiri Valeria V Marino Maria M Acconcia Filippo F

PloS one 20140415 4

The homeostatic control of the cellular proteome steady-state is dependent either on the 26S proteasome activity or on the lysosome function. The sex hormone 17β-estradiol (E2) controls a plethora of biological functions by binding to the estrogen receptor α (ERα), which is both a nuclear ligand-activated transcription factor and also an extrinsic plasma membrane receptor. Regulation of E2-induced physiological functions (e.g., cell proliferation) requires the synergistic activation of both tran ...[more]

PMID: 24736371

Similar Datasets

Project description:Rationale17β-Estradiol (E2) attenuates hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension (HPH) through an unknown mechanism that may involve estrogen receptors (ER) or E2 conversion to catecholestradiols and methoxyestradiols with previously unrecognized effects on cardiopulmonary vascular remodeling.ObjectivesTo determine the mechanism by which E2 exerts protective effects in HPH.MethodsMale rats were exposed to hypobaric hypoxia while treated with E2 (75 μg/kg/d) or vehicle. Subgroups were cotreated with pharmacologic ER-antagonist or with inhibitors of E2-metabolite conversion. Complementary studies were performed in rats cotreated with selective ERα- or ERβ-antagonist. Hemodynamic and pulmonary artery (PA) and right ventricular (RV) remodeling parameters, including cell proliferation, cell cycle, and autophagy, were measured in vivo and in cultured primary rat PA endothelial cells.Measurements and main resultsE2 significantly attenuated HPH endpoints. Hypoxia increased ERβ but not ERα lung vascular expression. Co-treatment with nonselective ER inhibitor or ERα-specific antagonist rendered hypoxic animals resistant to the beneficial effects of E2 on cardiopulmonary hemodynamics, whereas ERα- and ERβ-specific antagonists opposed the remodeling effects of E2. In contrast, inhibition of E2-metabolite conversion did not abolish E2 protection. E2-treated hypoxic animals exhibited reduced ERK1/2 activation and increased expression of cell-cycle inhibitor p27(Kip1) in lungs and RV, with up-regulation of lung autophagy. E2-induced signaling was recapitulated in hypoxic but not normoxic endothelial cells, and was associated with decreased vascular endothelial growth factor secretion and cell proliferation.ConclusionsE2 attenuates hemodynamic and remodeling parameters in HPH in an ER-dependent manner, through direct antiproliferative mechanisms on vascular cells, which may provide novel nonhormonal therapeutic targets for HPH.

Dataset Information

Lysosomal function is involved in 17?-estradiol-induced estrogen receptor ? degradation and cell proliferation.

Publications

Lysosomal function is involved in 17β-estradiol-induced estrogen receptor α degradation and cell proliferation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets