Molecular Endocrinology, Vol 9, 1500-1509, Copyright © 1995 by Endocrine Society

ARTICLES

Glucocorticoid regulation of cyclin D3 gene transcription and mRNA stability in lymphoid cells

D Reisman and EA Thompson
Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston 77550-0645, USA.

Glucocorticoids cause G0/G1 arrest of lymphoid cells. This is due, at least in part, to a decrease in the abundance of the G1 progression factor, cyclin D3. The mRNA encoding cyclin D3 (CcnD3 mRNA) is rapidly down-regulated when dexamethasone is added to P1798 murine T lymphoma cells. Fifty percent maximum inhibition is observed within about 2 h. Maximum inhibition of 75-85% obtains within 4-5 h. Cyclin D3 protein has a half-life of about 0.5 h in P1798 cells. Consequently, the abundance of cyclin D3 protein decreases in parallel with the abundance of CcnD3 mRNA. The effects of glucocorticoids are reversible. CcnD3 mRNA returns to near control levels within 2-3 h after removal of dexamethasone. Cyclin D3 protein recovers somewhat more slowly. The data indicate that glucocorticoids regulate the abundance of cyclin D3 mRNA. There is no significant decrease in nuclear run-on transcription of CcnD3 within 6 h after addition of glucocorticoids, although transcription is inhibited more than 80% after 24 h in the presence of dexamethasone. CcnD3 mRNA is very stable in mid-log phase P1798 cells, with a half-life of more than 8 h. The half-life of CcnD3 mRNA in glucocorticoid-treated cells is less than 1 h. Actinomycin D blocks the effects of glucocorticoids, suggesting that dexamethasone induces a substance that increases the turnover rate of CcnD3 mRNA. Regulation of CcnD3 mRNA abundance and of CcnD3 transcription has been studied in cells arrested at the G1/S interface by thymidine blockade. Glucocorticoids down-regulate CcnD3 mRNA in the absence of cell cycle progression. This observation indicates that glucocorticoid inhibition of cyclin D3 expression is not a secondary consequence of cell cycle arrest. However, glucocorticoids have no significant effect on transcription of CcnD3 in G1/S phase-arrested cells. Inhibition of transcription of CcnD3 is a delayed response and probably reflects withdrawal into a G0 state, rather than any proximal consequence of glucocorticoid action. Destabilization of CcnD3 mRNA appears to be a direct effect of glucocorticoids, independent of cell cycle progression, and mediated by a glucocorticoid-induced protein(s) that accelerates the degradation of CcnD3 mRNA.

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