Genes mediating glucocorticoid effects and mechanisms of their regulation

Geley, Stephan; Fiegl, Michael; Hartmann, Bernd L.; Kofler, Reinhard

doi:10.1007/3-540-61343-9_7

Cited by 27 publications

(24 citation statements)

References 579 publications

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“…5,6 Upon ligand binding, the activated GR translocates into the nucleus, where it acts as a sequence-specific transcription factor to induce or repress the expression of a large number of target genes. [7][8][9][10] Alternatively, the GR can influence gene expression without directly interacting with DNA through proteinprotein interaction with a number of transcription factors and co-factors. 11 The subsequent alterations in gene expression are considered responsible for GC induction of cell death and cell cycle arrest, another important antileukemic GC effect.…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoid receptor heterozygosity combined with lack of receptor auto-induction causes glucocorticoid resistance in Jurkat acute lymphoblastic leukemia cells

et al. 2004

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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. GR R477H ligand-bindingdependent nuclear import, as revealed by live-cell microscopy of YFP-tagged GR, was unaffected. Transactivation and transrepression were markedly impaired; however, GR R477H 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 autoinduce 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.

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Section: Introductionmentioning

confidence: 99%

Glucocorticoid receptor heterozygosity combined with lack of receptor auto-induction causes glucocorticoid resistance in Jurkat acute lymphoblastic leukemia cells

et al. 2004

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“…13 Associated with the wide range of GC effects, a few hundred genes have been identified that are GC-regulated. 14 In oncological disorders, GC function is mainly based on induction of cell death. [15][16][17] The GR has been the subject of intensive investigations, which aimed at identifying the cause of GC resistance.…”

Section: Introductionmentioning

confidence: 99%

Expression of heat-shock protein 90 in glucocorticoid-sensitive and -resistant childhood acute lymphoblastic leukaemia

et al. 2003

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Early reduction of leukaemic cells by chemotherapy is a strong predictor for treatment outcome in childhood acute lymphoblastic leukaemia (ALL). In ALL-(Berlin-Frankfurt-Mü nster) trials, early treatment response is assessed by the in vivo response to glucocorticoids (prednisone response, PR), the molecular background of which is unknown. The intracellular effects of glucocorticoids (GCs) are mediated by the glucocorticoid receptor (GR). In the absence of GC, the inactive GR resides within a multiprotein complex, consisting predominantly of the chaperone protein hsp90 (heat-shock protein 90). Until now, studies targeting GC resistance mainly focused on GR disorders and alterations of genes known to be associated with drug resistance. In addition, the GR multiprotein complex was associated with GC resistance in in vitro studies. We performed a case-control study for PR to investigate the association of in vivo GC resistance and hsp90 expression in childhood ALL. Hsp90 expression was assessed using a realtime PCR approach (Taqman technology) and Western blot technology. In this setting, we found no association of in vivo GC resistance and hsp90 expression. Therefore, we conclude that the expression of hsp90, the major component of the GR activating complex, is of minor importance for the in vivo GC resistance in childhood ALL.

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“…The GC down-or upregulated genes that actually mediate the`private pathway' of this death response are not known. A set of GC-regulated candidate genes has been identi®ed by various approaches (reviewed in Geley et al, 1996a), including the GC-repressed c-myc (Thulasi et al, 1993) and the GC-induced c-jun (Zhou and Thompson, 1996) genes, but their precise role, if any, in GC-induced apoptosis needs to be established. Concerning the execution phase (`common pathway'), GC-triggered cell death is associated with caspase activation (Neamati et al, 1995;Zhivotovsky et al, 1995;Geley et al, 1997b;Robertson et al, 1997), as are most forms of apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Bcl-2 interferes with the execution phase, but not upstream events, in glucocorticoid-induced leukemia apoptosis

et al. 1999

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Genes mediating glucocorticoid effects and mechanisms of their regulation

Cited by 27 publications

References 579 publications

Glucocorticoid receptor heterozygosity combined with lack of receptor auto-induction causes glucocorticoid resistance in Jurkat acute lymphoblastic leukemia cells

Glucocorticoid receptor heterozygosity combined with lack of receptor auto-induction causes glucocorticoid resistance in Jurkat acute lymphoblastic leukemia cells

Expression of heat-shock protein 90 in glucocorticoid-sensitive and -resistant childhood acute lymphoblastic leukaemia

Bcl-2 interferes with the execution phase, but not upstream events, in glucocorticoid-induced leukemia apoptosis

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