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(The FASEB Journal. 1999;13:169-180.)
© 1999 FASEB

Research Communications

Dysfunctional glucocorticoid receptor with a single point mutation ablates the CCAAT/enhancer binding protein-dependent growth suppression response in a steroid-resistant rat hepatoma cell variant

Ross A. Ramosa, William J. Meilandta, Edward C. Wanga and Gary L. Firestonea,1

a Department of Molecular and Cell Biology and The Cancer Research Laboratory, University of California at Berkeley, Berkeley, California 94720, USA

We used glucocorticoid-resistant and -sensitive hepatoma cell variants to characterize the mechanism of hepatoma cell resistance to the growth inhibitory effects of glucocorticoids. BDS1 hepatoma cells express transcriptionally active glucocorticoid receptors and undergo a stringent G1 cell cycle arrest in response to glucocorticoids that is dependent on the induced expression of the CCAAT/enhancer binding protein {alpha} (C/EBP{alpha}) transcription factor. In contrast, EDR1 hepatoma cells, which express normal levels of glucocorticoid receptors, fail to growth arrest or express C/EBP{alpha} when treated with glucocorticoids. Ectopic expression of wild-type rat glucocorticoid receptors into EDR1 cells restored the growth suppression response, suggesting a defect in the EDR1 receptor. DNA sequence analysis revealed a single point mutation causing a cysteine-to-tyrosine substitution at amino acid position 457 (C457Y-GR) in the zinc finger region of the glucocorticoid receptor that mediates both receptor–DNA and receptor–protein interactions. Glucocorticoid activation of the {alpha}1-acid glycoprotein (AGP) promoter, a liver acute-phase response gene, requires receptor–DNA binding as well as an interaction with C/EBP{alpha}. In contrast to the wild-type glucocorticoid receptor, ectopic expression of C/EBP{alpha} in EDR1 cells, or coexpression of C/EBP{alpha} along with the C457Y-GR into receptor-deficient EDR3 cells was required to partially restore glucocorticoid responsiveness of the AGP promoter by the EDR1 glucocorticoid receptor. Constitutive expression of the wild-type glucocorticoid receptor, but not the C457Y-GR mutant, was sufficient to restore the glucocorticoid growth suppression response to receptor-deficient EDR3 cells. Thus, we have identified a glucocorticoid-resistant hepatoma cell variant with a single point mutation in the zinc finger region of the glucocorticoid receptor gene that ablates the glucocorticoid growth suppression response and attenuates transcriptional activation of the AGP promoter.—Ramos, R. A., Meilandt, W. J., Wang, E. C., Firestone, G. L. Dysfunctional glucocorticoid receptor with a single point mutation ablates the CCAAT/enhancer binding protein-dependent growth suppression response in a steroid-resistant rat hepatoma cell variant. FASEB J. 13, 169–180 (1999)


Key Words: glucocorticoid receptor mutation • C/EBP{alpha}2 • steroid resistance • growth suppression




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