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Titolo:
GRKO mice express an aberrant dexamethasone-binding glucocorticoid receptor, but are profoundly glucocorticoid resistant
Autore:
Cole, TJ; Myles, K; Purton, JF; Brereton, PS; Solomon, NM; Godfrey, DI; Funder, JW;
Indirizzi:
Baker Med Res Inst, Prahran, Vic 3181, Australia Baker Med Res Inst Prahran Vic Australia 3181 rahran, Vic 3181, Australia Monash Univ, Sch Med, Dept Pathol & Immunol, Prahran, Vic 3181, Australia Monash Univ Prahran Vic Australia 3181 unol, Prahran, Vic 3181, Australia
Titolo Testata:
MOLECULAR AND CELLULAR ENDOCRINOLOGY
fascicolo: 1-2, volume: 173, anno: 2001,
pagine: 193 - 202
SICI:
0303-7207(20010228)173:1-2<193:GMEAAD>2.0.ZU;2-W
Fonte:
ISI
Lingua:
ENG
Soggetto:
TARGETED DISRUPTION; MINERALOCORTICOID RECEPTOR; FEEDBACK-CONTROL; GENE DISRUPTION; MESSENGER-RNA; MOUSE; TRANSLATION; MUTATIONS;
Keywords:
glucocorticoids; gene-targeting; glucocorticoid receptors;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
35
Recensione:
Indirizzi per estratti:
Indirizzo: Cole, TJ Baker Med Res Inst, Commercial Rd, Prahran, Vic 3181, Australia Baker Med Res Inst Commercial Rd Prahran Vic Australia 3181 ralia
Citazione:
T.J. Cole et al., "GRKO mice express an aberrant dexamethasone-binding glucocorticoid receptor, but are profoundly glucocorticoid resistant", MOL C ENDOC, 173(1-2), 2001, pp. 193-202

Abstract

The introduction of a targeted insertion mutation into exon 2 of the gel-it coding for thr glucocorticoid receptor (GR) enabled production of glucocorticoid receptor knock-out (GRKO) mice. GRKO mice on a C57BL/6/129sv mixed genetic background show a variable phenotype. with 90% of -/- mice dying atbirth with respiratory insufficiency but 10% of mutant mice surviving to maturity. To investigate the possibility of residual GR expression in surviving GRKO mice wt: have measured binding of the synthetic glucocorticoid dexamethasone in tissue extracts from adrenalectomized mice. High affinity binding of dexamethasone in protein extracts of liver. kidney. lung and brain from adult GRKO mice is found at levels 30-60% those in wild-type mice. with heterozygotes (+/-) having intermediate levels. PCR and ribonuclease protection analysis showed comparable levels of GR mRNA on the 3' side of the gene-targeted insertional mutation in exon 2 of the GR gene, with almost no GR mRNA detected from exons 1 and 2 on the 5' side of the gene-targeted insertional mutation, Western blot analysis using a C-terminal specific GR antibody detects a 39 kDa GR fragment in extracts from adult GRKO mice. Despite the evidence for expression of a ligand-binding domain fragment of the glucocorticoid receptor these mice are profoundly glucocorticoid resistant. with elevated levels of plasma ACTH and corticosterone. Thymocytes from adult and fetal GRKO mice are resistant to dexamethasone-induced apoptosis and cultured fetal hepatocytes from GRKO mice are completely refractory to glucocorticoid induction of the gluconeogenic enzyme glucose-6-phosphatase. Thus although the surviving adult homozygous GRKO mice express a dexamethasone-binding GR fragment, their classic target tissues remain profoundly glucocorticoid insensitive. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 21/05/18 alle ore 13:09:25