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The inhibition of commitment of mouse erythroleukemia cells by steroids involves a glucocorticoid-receptor mediated
Abstract:
Dexamethasone has been shown to inhibit dimethylsulfoxide (DMSO)-induced differentiation of mouse erythroleukemia (or Friend) cells by blocking commitment to terminal erythroid maturation. In this study, we confirmed previous reports indicating the presence of glucocorticoid receptors in murine erythroleukemia cells and examined the mechanism(s) by which steroids block commitment. Untreated murine erythroleukemia cells contain dexamethasone receptors which decrease in number during DMSO-induced cell differentiation. When steroids of different classes (estrogenic, androgenic, glucocorticoid) were tested for inhibition of commitment and for displacement of [3H]dexamethasone from its receptors in DMSO-treated cells, we observed that the glucocorticoids dexamethasone, prednisolone and hydrocortisone, all blocked commitment and substantially displaced [3H]dexamethasone. In contrast, steroids other than glucocorticoids failed to inhibit commitment or displace [3H]dexamethasone. Analysis of kinetics of dexamethasone binding to chromatin revealed that dexamethasone binds to the nucleus via the receptor and preferentially interacts with active chromatin. Inhibition of commitment by dexamethasone persisted in cells released from this agent and reincubated with DMSO in the presence of another glucocorticoid of similar affinity to steroid receptors; inhibition of commitment, however, was not obtained when cells removed from dexamethasone were incubated in the presence of beta-estradiol, progesterone and testosterone. These data indicate that inhibition of commitment of mouse erythroleukemia cells by steroids is associated with binding to glucocorticoid receptors and may involve interactions of steroids and their receptors with regions of chromatin.
Insights
Glucocorticoids like dexamethasone block erythroid maturation in mouse cells by binding to specific receptors. This action inhibits cell differentiation, offering insights into steroid-mediated cellular processes.
Area of Science:
- Cell Biology
- Molecular Endocrinology
- Cancer Research
Background:
- Dimethyl sulfoxide (DMSO) induces differentiation in mouse erythroleukemia cells.
- Dexamethasone inhibits this DMSO-induced differentiation by blocking commitment to terminal erythroid maturation.
- Glucocorticoid receptors are present in these cells.
Purpose of the Study:
- To investigate the mechanisms by which steroids, specifically glucocorticoids, inhibit cell commitment.
- To confirm the presence and role of glucocorticoid receptors in this process.
- To explore the interaction of steroids with chromatin during differentiation.
Main Methods:
- Testing various steroid classes (glucocorticoids, estrogenic, androgenic) for their ability to inhibit commitment and displace [3H]dexamethasone.
- Analyzing the kinetics of dexamethasone binding to chromatin.
- Observing the persistence of inhibition after dexamethasone removal and re-exposure to DMSO with different steroids.
Main Results:
- Glucocorticoids (dexamethasone, prednisolone, hydrocortisone) inhibited commitment and displaced [3H]dexamethasone.
- Non-glucocorticoid steroids did not inhibit commitment or displace the labeled hormone.
- Dexamethasone binds to the nucleus via its receptor and interacts with active chromatin.
- Inhibition persisted with other glucocorticoids but not with estrogenic, androgenic, or progestogenic steroids.
Conclusions:
- Steroid-induced inhibition of mouse erythroleukemia cell commitment is mediated by glucocorticoid receptors.
- This inhibition likely involves the interaction of steroids and their receptors with specific chromatin regions.
- The findings elucidate a specific molecular mechanism for steroid action on cell differentiation.