Imbalanced Expression of the Glucocorticoid Receptor Isoforms in Cultured Lymphocytes from a Patient with Systemic Glucocorticoid Resistance and Chronic Lymphocytic Leukemia

Shahidi, Homayoun; Vottero, Alessandra; Stratakis, Constantine A.; Taymans, Susan E.; Karl, Michael; Longui, Carlos Alberto; Chrousos, George P.; Daughaday, William H.; Gregory, Stephanie A.; Plate, Janet M. D.

doi:10.1006/bbrc.1998.9980

Cited by 109 publications

(65 citation statements)

References 24 publications

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“…We have used two measures of glucocorticoid sensitivity based on MTT assay: IC 50 as the point at which cell number was 50% of control untreated cells, and the lower asymptote of the dose-response curves representing the percentage of resistant cells in the sample. In very resistant or sensitive samples where IC 50 values fell outside of the prednisolone concentration range, these were recorded as 10 −4 m or 10 −9 m, respectively.…”

Section: Glucocorticoid Sensitivity In All and Cll Cellsmentioning

confidence: 99%

“…In very resistant or sensitive samples where IC 50 values fell outside of the prednisolone concentration range, these were recorded as 10 −4 m or 10 −9 m, respectively. In ALL blasts, prednisolone had a median IC 50 of 3 × 10 −4 m (Figure 1).…”

Section: Glucocorticoid Sensitivity In All and Cll Cellsmentioning

confidence: 99%

“…In ALL blasts, prednisolone had a median IC 50 of 3 × 10 −4 m (Figure 1). Blasts tended to be either sensitive or resistant to prednisolone in vitro with few intermediate IC 50 values. Conversely, the majority of blast samples from patients with CLL were resistant to prednisolone (median IC 50 10 −5 m) but with other values spread throughout the concentration range (10 −4 m to 10 −11 m).…”

Section: Glucocorticoid Sensitivity In All and Cll Cellsmentioning

confidence: 99%

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The role of AP-1 in glucocorticoid resistance in leukaemia

et al. 2001

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Glucocorticoids are used in the treatment of acute lymphoblastic leukaemia (ALL) and chronic lymphocytic leukaemia (CLL) but many patients develop glucocorticoid resistance on relapse. The ligand-activated glucocorticoid receptor inhibits activity of the AP-1 transcription factor and the purpose of this study was to test the hypothesis that up-regulation or overexpression of AP1-binding activity may be an important mechanism of glucocorticoid resistance in ALL and CLL. In vitro sensitivity of patient blasts to prednisolone was measured using the MTT assay. AP-1 levels were quantified by gel shift analysis and Fos and Jun levels were compared by Western blotting. To test for a relationship between glucocorticoid sensitivity and glucocorticoid-induced changes in AP-1 binding activity, leukaemic blasts were also treated with prednisolone before analysis.

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Section: Glucocorticoid Sensitivity In All and Cll Cellsmentioning

confidence: 99%

Section: Glucocorticoid Sensitivity In All and Cll Cellsmentioning

confidence: 99%

Section: Glucocorticoid Sensitivity In All and Cll Cellsmentioning

confidence: 99%

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The role of AP-1 in glucocorticoid resistance in leukaemia

et al. 2001

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“…[15][16][17] The GR has been the subject of intensive investigations, which aimed at identifying the cause of GC resistance. Studies with respect to receptor levels (sites/cell) in acute nonlymphoblastic leukaemia, 18 distribution of GR splice variants in asthmatic patients, 19 in chronic lymphocytic leukaemia 20 and in childhood ALL (own unpublished data, 2003), as well as studies in healthy subjects and childhood ALL patients investigating polymorphisms of genes known to be associated with drug resistance [21][22][23] all attributed to approach the cause of GC resistance. Furthermore, studies targeting the protein heterocomplex involved in the activation of the GR showed an association with GC resistance in human leukaemic cell lines and mouse fibroblasts.…”

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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“…Several studies with respect to specific targets like the glucocorticoid receptor (GR) and its splice variants, to proteins involved in the activation process of the GR and genetic variants of drug resistance genes or of the GR itself did not show any correlation between the results and the GC resistance. [21][22][23][24][25][26][27][28][29][30][31] In contrast to many proteome screening studies in human tissues, the advantage of the current study is that proteins were isolated from purified leukaemic cells that had all been processed and stored in the same manner. The minimum percentage of leukaemic blasts in the bone marrow of patients investigated was 77% before gradient centrifugation.…”

Section: Discussionmentioning

confidence: 99%

Unsupervised proteome analysis of human leukaemia cells identifies the Valosin-containing protein as a putative marker for glucocorticoid resistance

et al. 2006

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The response to initial glucocorticoid therapy in childhood acute lymphoblastic leukaemia (ALL) reliably predicts the response to multiagent chemotherapy. Patients resistant to glucocorticoids (prednisone poor responders (PPR)) have a poorer event-free survival compared to glucocorticoid-sensitive patients (prednisone good responders (PGR)). A casecontrol study was performed to investigate differential protein expression in leukaemic blasts from PGR and PPR childhood ALL patients. Two-dimensional gel electrophoresis (2-DE) was used for an unsupervised screening and surface enhanced laser desorption/ionisation-time of flight mass spectrometry (SELDI-TOF MS) for the characterisation of protein spots. In difference maps of average gels for the proteomes of each responder group, differentially expressed proteins were identified after tryptic digestion and spotting onto H4-SELDI-TOF-MS chips. Proteins overexpressed in PPR were Catalase, RING finger protein 22 alpha, Valosin-containing protein (VCP) and a G-protein-coupled receptor. Proteins overexpressed in PGR were protein kinase C and malate dehydrogenase. Valosincontaining protein was chosen for validation and quantification by Western blot analysis in a second case-control group of ALL patients. In this second independent cohort, median VCP expression (P 25 -P 75 ) was 0.15 (0.11-0.28) in PGR and 0.34 (0.14-0.99) in PPR patients (P ¼ 0.04). We conclude that high VCP expression is associated with poor prednisone response in childhood ALL patients.

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Imbalanced Expression of the Glucocorticoid Receptor Isoforms in Cultured Lymphocytes from a Patient with Systemic Glucocorticoid Resistance and Chronic Lymphocytic Leukemia

Cited by 109 publications

References 24 publications

The role of AP-1 in glucocorticoid resistance in leukaemia

The role of AP-1 in glucocorticoid resistance in leukaemia

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

Unsupervised proteome analysis of human leukaemia cells identifies the Valosin-containing protein as a putative marker for glucocorticoid resistance

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