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v-mos Oncoproteins Affect the Nuclear Retention and Reutilization of Glucocorticoid Receptors

Department of Biological Sciences, University of Pittsburgh Pittsburgh, Pennsylvania 15260

Address requests for reprints to: Dr. Donald DeFranco, University of Pittsburgh, Department of Biological Sciences, Pittsburgh, Pennsylvania 15260.

Abstract

Expression of the p85^gag-mos oncoprotein in temperature sensitive transformed 6m2 cells results in desensitization of glucocorticoid induction of metallothionein- 1 mRNA. Indirect immunofluorescence analyses demonstrate that hormone insensitivity in v-mos transformed cells is associated with inefficient nuclear retention of glucocorticoid receptor (GR) protein. Desensitized receptors that accumulate in the cytoplasm of transformed 6m2 cells do not regain the capacity for hormone-dependent nuclear translocation after turnover of the thermo-labile p85^gag-mos oncoprotein. Although ligand induced down-regulation of immunoreactive GR protein occurs in transformed 6m2 cells, desensitized receptors appear to retain some capacity to bind hormone in vivo. Thus alterations in the intracellular partitioning of GR protein in v-mos-transformed cells result in the generation of a novel desensitized receptor that is apparently trapped in the cytoplasm and incapable of being reutilized.

INTRODUCTION: Steroid hormone receptors are a class of enhancerbinding proteins that modulate transcription through sequence-specific interactions with hormone response elements (1, 2). As members of a supergene family of ligand-activated gene regulatory proteins (3, 4), steroid receptors are structurally related, being comprised of distinct, independently functional domains that specify ligand binding, DNA binding, and transcriptional activation activities (5–9).

FOOTNOTES

This work was supported by Grant CA-43037 from the NIH and by a Basil O'Connor Research Award from the March of Dimes Foundation.

Received for publication April 26, 1989. Revision received May 18, 1989. Accepted for publication May 18, 1989.

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