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Absence in Glucocorticoid-resistant Mouse Lymphoma P1798 of a Glucocorticoid Receptor Domain Responsible for Biological Effects¹

Department of Medical Nutrition, Karolinska Institute, Huddinge University Hospital F69, S-141 86 Huddinge, Sweden [S. O., J. C-D., Ö. W., J-Å. G.]; Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [Y-W. S.]; and American Cancer Society, New York, New York 10017 [J. S.]

Glucocorticoid-resistant (CR), in contrast to glucocorticoid-sensitive (CS), mouse lymphoma P1798 was shown to lack antiglucocorticoid receptor immunoactivity. Antibodies raised against the purified rat liver glucocorticoid receptor (GR) cross-reacted with the GR from CS, but not with the GR from CR, P1798 lymphoma. Using highly specific antisera against the GR in an indirect competitive enzyme-linked immunosorbent assay, it was demonstrated that -chymotrypsin digestion of the GR from CS P1798 lymphoma caused a separation of a "resistant-like" nonimmunogenic steroid and DNA-binding domain (Stockes' radius, 3.3 nm) from an immunoactive domain (Stokes' radius, 2.6 nm). In contrast to CS P1798 lymphoma, neither before nor after -chymotrypsin digestion, immunoactivity could be found in the cytosol from CR P1798 lymphoma. This was assayed after chromatography on DNA-cellulose or gel filtration on Agarose A (0.5 m). These results suggest that the domain of the CS GR containing the immunoactive determinant(s), normally removed by limited proteolysis by -chymotrypsin, appears to be missing in CR P1798 lymphoma cytosol. It seems that this domain plays an important role in the mechanism of action of glucocorticoids. This might suggest that a mutation has occurred affecting the genome resulting in defective transcription of the receptor gene(s) in CR P1798 lymphoma.

¹ The project was supported by funds provided in part by the Swedish Medical Research Council (Nos. 13X-2819 and 13X-06245).

² Recipient of funds from the International Cancer Research Data Bank Program of the National Cancer Institute, NIH, under International Cancer Research Technology Transfer Contract NO1-CO-65341 with the International Union against Cancer.

³ Recipient of a research fellowship from the Swedish Cancer Society.

Received 8/10/82. Accepted 3/30/83.