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Lymphoma cell variants of decreased glucocorticoid sensitivity
Abstract:
Glucocorticoid-sensitive S49.1 mouse lymphoma cells were mutagenized and cloned in soft agar containing 10 nM dexamethasone. A series of clones were grown and tested for growth inhibition by dexamethasone. While most clones were completely resistant to the steroid, some were sensitive but required significantly higher glucocorticoid concentrations for the same response than wild-type cells. Two of these low-sensitivity clones were used for binding studies; they showed significantly decreased levels of glucocorticoid receptors as compared to wild-type cells. The data support the view that the level of cellular steroid hormone receptors quantitatively controls hormone responsiveness in closely related cells.
Insights
Glucocorticoid-sensitive lymphoma cells were studied for resistance to dexamethasone. Lower glucocorticoid receptor levels were found in resistant cells, suggesting receptor quantity controls hormone response.
Area of Science:
- Cell biology
- Endocrinology
- Molecular pharmacology
Background:
- Glucocorticoids are critical regulators of cellular functions.
- Understanding mechanisms of steroid hormone resistance is crucial for therapeutic applications.
Purpose of the Study:
- To investigate the relationship between glucocorticoid receptor levels and cellular response to dexamethasone.
- To identify genetic alterations leading to altered glucocorticoid sensitivity in S49.1 mouse lymphoma cells.
Main Methods:
- S49.1 mouse lymphoma cells were mutagenized and selected for resistance to dexamethasone.
- Clones were tested for growth inhibition by varying dexamethasone concentrations.
- Glucocorticoid receptor binding studies were performed on selected clones.
Main Results:
- Most mutagenized clones exhibited complete resistance to dexamethasone.
- Some clones showed reduced sensitivity, requiring higher dexamethasone concentrations for growth inhibition.
- Low-sensitivity clones displayed significantly decreased glucocorticoid receptor levels compared to wild-type cells.
Conclusions:
- Cellular glucocorticoid receptor levels quantitatively influence hormone responsiveness.
- Reduced receptor expression is a key mechanism underlying glucocorticoid resistance in these cells.
- This study provides insights into the molecular basis of steroid hormone action and resistance.