Τίτλος:
Rho family guanine nucleotide exchange factor Brx couples extracellular
signals to the glucocorticoid signaling system
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Glucocorticoids regulate many crucial biologic functions through their
cytoplasmic/nuclear glucocorticoid receptors (GR). Excess, deficiency,
or alteration in tissue sensitivity to glucocorticoids has been
associated with major causes of human morbidity and mortality. Brx, a
cytoplasmic Rho family guanine nucleotide exchange factor, binds to and
influences the activity of several nuclear hormone receptors. We
examined the functional and molecular interactions between GR and Brx.
The glucocorticoid sensitivity of lymphocytes obtained from mice
haplo-insufficient for Brx was significantly decreased. Conversely,
GR-mediated transcriptional activity of a glucocorticoid response
element (GRE)-mediated glucocorticoid-responsive promoter was enhanced
by Brx in a guanine nucleotide exchange factor domain-dependent fashion.
Brx interacted with GR, forming a ternary complex with RhoA. In a
chromatin immunoprecipitation assay, Brx and RhoA were co-precipitated
with GREs only in the presence of ligand-activated GR. Extracellularly
administered lysophosphatidic acid, which activates its signaling
cascade through a specific membrane GTP-binding protein
(G-protein)-coupled receptor in a G-protein alpha(13)-, Brx-, and
RhoA-dependent fashion, enhanced GR transcriptional activity, whereas
depletion of endogenous Brx attenuated this effect. These findings
suggest that glucocorticoid signaling and, hence, the tissue sensitivity
to glucocorticoids, may be coupled to extracellular signals via Brx and
small G-proteins. Nuclear Brx might act as a local
GRE-GR-transcriptosome activator by mediating the effect of small
G-proteins on glucocorticoid-regulated genes.
Συγγραφείς:
Kino, T
Souvatzoglou, E
Charmandari, E
Ichijo, T and
Driggers, P
Mayers, C
Alatsatianos, A
Manoli, I and
Westphal, H
Chrousos, GP
Segars, JH
James, HS
Περιοδικό:
Journal of Biological Chemistry
Εκδότης:
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI:
10.1074/jbc.M509339200
