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c-Myc and Cyclin D3 (CcnD3) Genes Are Independent Targets for Glucocorticoid Inhibition of Lymphoid Cell Proliferation¹

Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, Texas 77550-0645

Glucocorticoids inhibit the expression of critical cell cycle-regulatory genes. The G₁ cyclin gene CcnD3, which encodes cyclin D3, is inhibited by dexamethasone in P1798 murine T lymphoma cells. Glucocorticoids also inhibit expression of the catalytic partner of cyclin D3, Cdk4. Inhibition of these two genes results in a decrease in the ability to phosphorylate the Rb-1 tumor suppressor gene product. Stable transformation with SV40 T antigen expression vectors prevents glucocorticoid-mediated cell cycle arrest, which is consistent with the conclusion that glucocorticoids inhibit Rb-1 phosphorylation. Overexpression of cyclin D3 suffices to restore Rb-kinase activity in glucocorticoid-treated cells. Nevertheless, overexpression of cyclin D3 does not prevent glucocorticoid inhibition of cell proliferation. Cells transformed with Cdk4 expression vectors, with or without cyclin D3 expression vectors, also undergo G₀ arrest in the presence of dexamethasone. Glucocorticoids inhibit c-Myc expression in lymphoid cells, and transient expression of c-Myc protein attenuates the lytic response in glucocorticoid-treated human leukemia cells (R. Thulasi, D. V. Harbour, and E. B. Thompson, J. Biol. Chem., 268: 18306–16312, 1993). However, P1798 cells stably transfected with c-Myc expression vectors are sensitive to glucocorticoid-mediated G₀ arrest. Such transformants withdraw from the cell cycle when treated with dexamethasone. P1798 cells were transformed so as to express both c-Myc protein and cyclin D3 in the presence of glucocorticoids. These Myc/D3 cells continue to proliferate in the presence of dexamethasone, and virtually all of these cells are capable of entering S phase in the presence of the steroid. Rapid apoptotic cell death occurs when wild-type P1798 cells are treated with dexamethasone in serum-free medium. Myc-transformed and cyclin D3-transformed cells also die rapidly when treated with glucocorticoids in the absence of serum. T antigen transformants are resistant to glucocorticoid-mediated apoptosis in serum-free medium. Double transformants that express both cyclin D3 and c-Myc are also resistant to apoptosis in the presence of dexamethasone. We conclude that inhibition of both CcnD3 and c-Myc genes is critical to glucocorticoid-mediated G₀ arrest. Furthermore, those genes that convey resistance to growth arrest also convey resistance to cell death.

¹ This work was supported in part by National Cancer Institute Grant R37-CA24347.

² Present address: Department of Genetics and Development, Columbia University College of Physicians and Surgeons, New York, NY.

³ Present address: Third Department of Internal Medicine, Tohoku University School of Medicine, Sendai 980, Japan.

⁴ To whom requests for reprints should be addressed, at Department of Human Biological Chemistry and Genetics, University of Texas-Galveston, Medical Branch, Basic Science Building, Galveston, TX 77550-0645.

Received 5/ 5/95. Accepted 7/19/95.

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