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- Title
Glucocorticoid receptor heterozygosity combined with lack of receptor auto-induction causes glucocorticoid resistance in Jurkat acute lymphoblastic leukemia cells.
- Authors
Riml, S.; Schmidt, S.; Ausserlechner, M.J.; Geley, S.; Kofler, R.
- Abstract
Glucocorticoids (GC) induce apoptosis in malignant lymphoblasts, but the mechanism of this process as well as that of the clinically important GC resistance is unknown. We investigated GC resistance in Jurkat T-ALL cells in which ectopic GC receptor (GR) restores GC sensitivity, suggesting deficient GR expression. Jurkat cells expressed one wild-type and one mutated (R477H) GR allele. GRR477H ligand-binding-dependent nuclear import, as revealed by live-cell microscopy of YFP-tagged GR, was unaffected. Transactivation and transrepression were markedly impaired; however, GRR477H did not act in a dominant-negative manner, that is, did not prevent cell death, when introduced into a GC-sensitive cell line by retroviral gene transfer. Contrary to another GR heterozygous, but GC-sensitive, T-ALL model (CCRF-CEM), Jurkats expressed lower basal GR levels and did not auto-induce their GR, as revealed by 'real-time' RT-PCR and immunoblotting. Absent GR auto-induction could not be restored by transgenic GR and, hence, was not caused by reduced basal GR levels. Thus, inactivation of one GR gene results in haploinsufficiency if associated with lack of GR auto-induction.Cell Death and Differentiation (2004) 11, S65-S72. doi:10.1038/sj.cdd.4401413 Published online 12 March 2004
- Subjects
GLUCOCORTICOID receptors; CELL death; LYMPHOBLASTIC leukemia treatment; DRUG resistance in cancer cells; APOPTOSIS; CELL lines
- Publication
Cell Death & Differentiation, 2004, Vol 11, pS65
- ISSN
1350-9047
- Publication type
Article
- DOI
10.1038/sj.cdd.4401413