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Dual Regulation of Protein Maturation in Viral Infected Rat HTC Hepatoma Cells by Glucocorticoids and Progesterone

Sandra D. Winguth^* and Gary L. Fireston

Department of Physiology-Anatomy and Cancer Research Laboratory, University of California, Berkeley Berkeley, California 94720

Address requests for reprints to: Gary L. Firestone, Department of Physiology-Anatomy, University of California, Berkeley, California 94720.

Abstract

Dexamethasone, a synthetic glucocorticoid, is required for full posttranslational maturation of mouse mammary tumor virus (MMTV) phosphoproteins and glycoproteins in M1.54 cells, a viral infected rat hepatoma (HTC) cell line. Pulse-chase radiolabeling with [³⁵S]methionine revealed that steroids with known glucocorticoid activity (such as dexamethasone and hydrocortisone) regulated the maturation of both MMTV polyproteins in a manner proportional to their occupancy for glucocorticoid receptors and their biological potency. In contrast, progesterone selectively induced the proteolytic processing of MMTV phosphoproteins but simultaneously antagonized the dexamethasone-regulated maturation of MMTV glycoproteins and all other tested glucocorticoid responses. Exposure to suboptimal concentrations of both progesterone and dexamethasone fully stimulated the processing of MMT phosphoproteins, suggesting that steroid receptors occupied with combinations of either steroid functionally interact at the putative maturation gene. Moreover, treatment with either actinomycin D, apotent inhibitor of de novo RNA synthesis, or RU38486, a synthetic antagonist of glucocorticoid andprogesterone action, prevented both the dexamethasone and progesterone-regulated inductionof MMTV phosphoprotein maturation. Sedimentation velocity and saturation binding analysis revealed that the sizes and concentrations of hepatoma cell progesterone and dexamethasone binding activities are similar while specific binding of the active progestin R5020 was not detected in either M1.54 cells or the glucocorticoid receptor deficient HTC cell line MSN6.10.2. Taken together, our results demonstrate that two distinct classes of steroid hormones can uniquely alter the posttranslationalmaturation of a specific subset of phosphoprotein substrates by a common glucocorticoid receptor-dependent process

FOOTNOTES

This research was supported by Grant DCB-8616446 from the National Science Foundation.

^* Predoctoral trainee supported by a National Research Service Grant (CA-09041) awarded by the NIH.

Recipient of a National Science Foundation Presidential Young Investigator Award (DCD-8351884).

Received for publication June 4, 1987. Accepted for publication September 8, 1987.

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