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@ARTICLE{Zhang:13100,
author = {Zhang, G. and Yanamala, N. and Lathrop, KL. and Zhang, L.
and Klein-Seetharaman, J. and Srinivas, H.},
title = {{L}igand-independent antiapoptotic function of estrogen
receptor-beta in lung cancer cells},
journal = {Molecular endocrinology},
volume = {24},
issn = {0888-8809},
address = {Bethesda, Md.},
publisher = {Endocrine Society},
reportid = {PreJuSER-13100},
pages = {1737 - 1747},
year = {2010},
note = {This work was supported by the Career Development Award
from the University of Pittsburgh Specialized Program of
Research Excellence (SPORE) in Lung Cancer and by the Core
Grant for Vision Research EY08098.},
abstract = {Recent studies have demonstrated the presence of estrogen
receptor (ER)beta in the mitochondria in various cell types
and tissues, but the exact function of this localization
remains unclear. In this study, we have examined the
function of mitochondrial ERbeta in non-small-cell lung
cancer (NSCLC) cells. Down-regulation of ERbeta by short
hairpin RNA constructs sensitized NSCLC cells to various
apoptosis-inducing agents such as cisplatin, taxol, and
etoposide. The increased growth inhibition and induction of
apoptosis in ERbeta-knockdown cells was observed
irrespective of estrogen treatment, suggesting a
ligand-independent role of ERbeta in regulating the
intrinsic apoptotic pathway. Further, ERbeta from the
mitochondrial fraction physically interacted with the
proapoptotic protein Bad, in a ligand-independent manner.
Glutathione-S-transferase pull-down assays and molecular
modeling studies revealed that the DNA-binding domain and
hinge region of ERbeta, and the BH3 domain of Bad were
involved in these interactions. Further investigations
revealed that ERbeta inhibited Bad function by disrupting
Bad-Bcl-X(L) and Bad-Bcl-2 interactions. Reintroduction of
ERbeta in the mitochondria of ERbeta knockdown cells
reversed their sensitivity to cisplatin. Overall, our
results demonstrate a ligand-independent role of ERbeta in
regulating apoptosis, revealing a novel function for ERbeta
in the mitochondria.},
keywords = {Apoptosis: drug effects / Carcinoma, Non-Small-Cell Lung:
metabolism / Carcinoma, Non-Small-Cell Lung: pathology /
Cell Line, Tumor / Cell Survival: drug effects / Cisplatin:
pharmacology / Estrogen Receptor beta: chemistry / Estrogen
Receptor beta: metabolism / Gene Knockdown Techniques /
Humans / Immunoprecipitation / Inhibitory Concentration 50 /
Ligands / Lung Neoplasms: metabolism / Lung Neoplasms:
pathology / Mitochondria: drug effects / Mitochondria:
metabolism / Models, Biological / Models, Molecular /
Protein Binding: drug effects / Protein Structure, Tertiary
/ Protein Transport: drug effects / RNA, Small Interfering:
metabolism / bcl-Associated Death Protein: chemistry /
bcl-Associated Death Protein: metabolism / bcl-X Protein:
metabolism / Estrogen Receptor beta (NLM Chemicals) /
Ligands (NLM Chemicals) / RNA, Small Interfering (NLM
Chemicals) / bcl-Associated Death Protein (NLM Chemicals) /
bcl-X Protein (NLM Chemicals) / Cisplatin (NLM Chemicals) /
J (WoSType)},
cin = {ISB-2},
ddc = {610},
cid = {I:(DE-Juel1)ISB-2-20090406},
pnm = {BioSoft: Makromolekulare Systeme und biologische
Informationsverarbeitung},
pid = {G:(DE-Juel1)FUEK505},
shelfmark = {Endocrinology $\&$ Metabolism},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:20660297},
pmc = {pmc:PMC2940472},
UT = {WOS:000281387300005},
doi = {10.1210/me.2010-0125},
url = {https://juser.fz-juelich.de/record/13100},
}