Document Detail


Identification of the activation-labile gene: a single point mutation in the human glucocorticoid receptor presents as two distinct receptor phenotypes.
MedLine Citation:
PMID:  8316249     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
CCRF-CEM-C7 is a well characterized human leukemic clonal cell line which is lysed by dexamethasone (dex). Originating from the wild-type CEM-C7 cells are two dex-resistant clones which are not lysed by 1 microM dex and have functionally defective glucocorticoid receptors (GR). They are receptorless ICR27TK.3 and activation-labile 4R4 cells. ICR27TK.3 and 4R4 cells have distinct cellular phenotypes, as indicated by dissimilar numbers of dex-binding sites despite similar levels of GR mRNA and immunochemically detectable GR. We have now investigated the molecular defects in the GR of ICR27TK.3 and 4R4 cells by determining the nucleotide sequence of their GR. Our results support the biochemical evidence previously reported by others for the presence of both a normal (GR+) and a mutant (GR*) allele in CEM-C7 cells. We clearly show that the wild-type CEM-C7 cells express two alleles of GR, the normal GR+ and the abnormal GR*, which has a Leu753--> Phe753 mutation. We demonstrate that both ICR27TK.3 and 4R4 cells contain only the abnormal GR* and that the normal GR+ gene is deleted in both of these GR defective clones. Our results further show that the GR* is basically an activation-labile receptor and has diminished functional capability in a transfection assay measuring GR-driven transcription. Thus, these two phenotypically different cell lines express similar amounts of an identical GR* containing a single point mutation at amino acid 753. A single point mutation in the steroid-binding domain of the GR, therefore, may behave differently, depending on the cellular milieu in which it is expressed.
Authors:
J Ashraf; E B Thompson
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Molecular endocrinology (Baltimore, Md.)     Volume:  7     ISSN:  0888-8809     ISO Abbreviation:  Mol. Endocrinol.     Publication Date:  1993 May 
Date Detail:
Created Date:  1993-07-23     Completed Date:  1993-07-23     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  8801431     Medline TA:  Mol Endocrinol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  631-42     Citation Subset:  IM    
Affiliation:
Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston 77550-0645.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Base Sequence
Cloning, Molecular
Dexamethasone / metabolism,  pharmacology
Drug Resistance
Humans
Leukemia / genetics
Molecular Sequence Data
Phenotype
Plasmids
Point Mutation*
Polymerase Chain Reaction
RNA, Messenger / metabolism
Receptors, Glucocorticoid / genetics*
Sequence Analysis, DNA
Transfection
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
CA-41407/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/RNA, Messenger; 0/Receptors, Glucocorticoid; 50-02-2/Dexamethasone

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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