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Glucocorticoid effect on oncogene/growth gene expression in human T lymphoblastic leukemic cell line CCRF-CEM.
1Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston 77550.
Abstract:
Glucocorticoids induce growth inhibition and eventually cause cell lysis in certain sensitive leukemic cells. To investigate how glucocorticoids interact with cell growth pathways, we studied the expression of 14 growth-related genes in dexamethasone-treated CEM-C7A cells, a steroid-sensitive clone of the CCRF-CEM cell line, and in several closely related clones. The 14 genes studied were chosen to represent four different levels of mitogenic signal transduction. Detectable mRNA levels were found for 8 of the 14 genes, but among these only c-myc expression was obviously suppressed by dexamethasone. The c-myc mRNA levels declined abruptly during the first 12 h after addition of 1 microM dexamethasone, and maximal suppression occurred by 18 h. This change was not seen in the C7A controls, in the glucocorticoid-resistant, receptor-deficient clone ICR-27, or in the glucocorticoid-resistant, receptor-positive clone C1. H.10, a hybrid clone between C1 and ICR-27, showed restoration of the sensitive phenotype, and in H.10 cells the c-myc mRNA was also suppressed by dexamethasone. Our results suggest that: 1) functional glucocorticoid receptor is required for inducing c-myc suppression. 2) In dexamethasone-resistant cells with functional receptors c-myc is not suppressed. 3) The growth arrest induced by glucocorticoids correlates with, and may be regulated via, suppression of c-myc expression.
Insights
Glucocorticoids suppress c-myc gene expression in sensitive leukemia cells, a key step in their growth inhibition. This effect requires a functional glucocorticoid receptor and is linked to cell cycle arrest.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Glucocorticoids are known to inhibit the growth of sensitive leukemic cells.
- Understanding the molecular mechanisms behind glucocorticoid-induced growth arrest is crucial for leukemia treatment.
Purpose of the Study:
- To investigate the impact of glucocorticoids on growth-related gene expression in leukemia cells.
- To identify specific genes and pathways involved in glucocorticoid-mediated growth inhibition.
Main Methods:
- Studied the expression of 14 growth-related genes in dexamethasone-treated CEM-C7A cells and related clones.
- Analyzed c-myc mRNA levels using quantitative methods over time.
- Compared gene expression in steroid-sensitive and resistant cell lines.
Main Results:
- Dexamethasone significantly suppressed c-myc mRNA levels in sensitive leukemia cells within 18 hours.
- This suppression was dependent on a functional glucocorticoid receptor.
- Resistant cell lines, even with functional receptors, did not show c-myc suppression.
Conclusions:
- Functional glucocorticoid receptor is essential for dexamethasone-induced c-myc suppression.
- c-myc suppression is strongly correlated with glucocorticoid-induced growth arrest in leukemia cells.
- Targeting the c-myc pathway may offer therapeutic strategies for leukemia.