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Titolo:
GLUCOCORTICOID RECEPTOR STRUCTURE AND FUNCTION IN AN ADRENOCORTICOTROPIN-SECRETING SMALL-CELL LUNG-CANCER
Autore:
GAITAN D; DEBOLD CR; TURNEY MK; ZHOU P; ORTH DN; KOVACS WJ;
Indirizzi:
VANDERBILT UNIV,SCH MED,DIV ENDOCRINOL,ROOM 715 MED RES BLDG 2 NASHVILLE TN 37232 VANDERBILT UNIV,SCH MED,DIV ENDOCRINOL NASHVILLE TN 37232 DEPT VET AFFAIRS MED CTR NASHVILLE TN 37212
Titolo Testata:
Molecular endocrinology
fascicolo: 9, volume: 9, anno: 1995,
pagine: 1193 - 1201
SICI:
0888-8809(1995)9:9<1193:GRSAFI>2.0.ZU;2-7
Fonte:
ISI
Lingua:
ENG
Soggetto:
HORMONE PRODUCTION; RESISTANT; TRANSCRIPTION; INHIBITION; EXPRESSION; CARCINOMA; LINES;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
29
Recensione:
Indirizzi per estratti:
Citazione:
D. Gaitan et al., "GLUCOCORTICOID RECEPTOR STRUCTURE AND FUNCTION IN AN ADRENOCORTICOTROPIN-SECRETING SMALL-CELL LUNG-CANCER", Molecular endocrinology, 9(9), 1995, pp. 1193-1201

Abstract

ACTH secretion by tumors of nonpituitary origin is characteristicallyresistant to negative feedback regulation by glucocorticoids. One possible mechanism for the phenomenon could be a structural defect in theintracellular glucocorticoid receptor (GR). We studied the GR in DMS-79 cells derived from a human ACTH-secreting small cell lung cancer. Compared with control cells, DMS-79 cells were found to have greatly diminished GR ligand-binding activity and immunoreactive 94-kilodalton (kDa) GR content. Northern blot analysis revealed expression of GR transcripts that appeared to be slightly larger than those in control cells. A DMS-79 cell GR cDNA was cloned by reverse transcription/polymerase chain reaction amplification of mRNA using primers specific for full-length normal GR. The derived sequence of this full-length GR differed from the reported sequence by a single altered codon (G to A; Asn toSer at codon 363) outside the steroid-binding domain. This N363S DMS-79 GR functioned normally to activate a target gene [mouse mammary tumor virus-chloramphenicol acetyl transferase (MMTV-CAT)] in transient transfection experiments in COS cells. Evidence for expression of a second type of GR mRNA was obtained by screening a DMS-79 cell cDNA library. This GR cDNA contained normal GR sequence up to nucleotide 2155, corresponding exactly to the end of exon 7 in the normal GR gene. The sequence appended to the GR sequences was not matched by any known sequence in DNA databases and included an in-frame termination codon afteronly 6 bases. The predicted truncated GR protein product (GR Delta) has a mot wt of 73,740 and lacks most of the ligand-binding domain. Transient transfection of the GR Delta form into COS cells did not revealany dominant negative effect on the function of a cotransfected normal GR. GR signaling in DMS-79 cells could be restored by transient transfection with a normal GR cDNA. These data indicate that at least one GR allele is intact in DMS-79, that DMS-79 cells may produce the predominant truncated form of GR by aberrant splicing, and that the resultant diminution of normal GR expression may account for the clinically observed glucocorticoid-resistant state.

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Documento generato il 07/07/20 alle ore 06:05:08