Related Experiment Videos
Relationship between glucocorticoid-mediated early decrease of protein synthesis and the steady state decreases of
1Department of Biochemistry, College of Medicine, University of Vermont, Burlington, VT 05405, USA. Kenneth.Cutroneo@uvm.edu
Abstract:
The present studies were undertaken to better elucidate the mechanism(s) by which glucocorticoids inhibit the process of tissue repair. The aim was to determine the importance of the effect of glucocorticoids on decreasing the nuclear TGF-beta activator protein. The relationship amongst inhibition of noncollagen protein synthesis and the steady state levels of glucocorticoid receptor and the TGF-beta activator protein was examined. Both collagen and noncollagen synthesis were determined in skin fibroblast cell culture and in dermis. Fetal rat skin fibroblasts were treated for 24 h with dexamethsone. Noncollagen protein synthesis was decreased to approximately one-half that of collagen synthesis. Similar results were obtained in dermis in vivo. At 48 h, dexamethasone treatment resulted in practically no nuclear glucocorticoid receptor being noted and a 40-45% steady state decrease of the TGF-beta activator protein. We have recently reported that the TGF-beta activator protein exists as a protein complex with SP1 and NFKB (p 49). The present data indicate that although the marked decrease of the nuclear glucocorticoid receptor DNA binding following dexamethasone treatment is not comparable to the early 24 h decrease of noncollagen protein synthesis, the decrease of the TGF-beta activator protein complex binding to DNA is. The present studies indicate the importance of the effect of dexamethasone on the steady state level of the TGF-beta activator protein complex in the glucocorticoid-mediated process inhibition of tissue repair and the relationship of this decrease to the earlier inhibition of protein synthesis.
Insights
Glucocorticoids inhibit tissue repair by decreasing the TGF-beta activator protein complex. This reduction in the TGF-beta activator protein complex is linked to the early inhibition of protein synthesis during healing.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Glucocorticoids are known to inhibit tissue repair processes.
- The precise molecular mechanisms underlying this inhibition are not fully understood.
- Transforming growth factor-beta (TGF-beta) activator protein plays a role in tissue repair.
Purpose of the Study:
- To elucidate the mechanism by which glucocorticoids inhibit tissue repair.
- To determine the role of decreased nuclear TGF-beta activator protein in this process.
- To examine the relationship between protein synthesis inhibition and glucocorticoid receptor/TGF-beta activator protein levels.
Main Methods:
- Fetal rat skin fibroblasts were treated with dexamethasone (a glucocorticoid).
- Collagen and noncollagen protein synthesis were measured in cell culture and in vivo (dermis).
- Nuclear glucocorticoid receptor and TGF-beta activator protein levels and DNA binding were assessed.
Main Results:
- Dexamethasone treatment decreased noncollagen protein synthesis by approximately 50% within 24 hours.
- At 48 hours, dexamethasone treatment led to minimal nuclear glucocorticoid receptor and a 40-45% decrease in TGF-beta activator protein.
- The decrease in TGF-beta activator protein complex binding to DNA correlated with the inhibition of protein synthesis.
Conclusions:
- Dexamethasone significantly reduces noncollagen protein synthesis, impacting tissue repair.
- The reduction in the steady-state level of the TGF-beta activator protein complex is crucial for glucocorticoid-mediated inhibition of tissue repair.
- This decrease in the TGF-beta activator protein complex is related to the early inhibition of protein synthesis.