Development of Resistance to Glucocorticoid Hormones during Rat Thymus Cell Differentiation: Proteins Associated with Emergence of the Resistant State1

Two-dimensional gel electrophoresis was used to detect [36S]methionine-labeled newly synthesized proteins from both glucocorticoid-sensitive and -resistant thymus cells. Normal thymic lymphocytes were taken for the sensitive population; the resistant population was composed of medullary thymocytes obtained from rats treated with dexamethasone (10 mg per kg body weight per day) for 3 days. When the proteins from glucocorticoid-sensitive cells are compared to those from re sistant cells, the majority of the =1000 proteins were similar; however, 18 proteins were different. There were 13 proteins that increase in the resistant state and 5 that decrease. One major change is the appearance of a new protein with a molecular weight of about 36,000 in resistant rat thymocytes. This protein is in the same position on the gels as is a protein found in corticosteroid-resistant P1798 mouse lymphosarcoma cells but not in the corticosteroid-sensitive cells. Control ex periments indicate that the protein differences are neither components of fibrous tissue associated with the cells nor components of blood. Changes in the synthesis of a common set of proteins that are characteristic of the hormone-resistant state suggest that the presence of one or more of these proteins may confer resistance. The appearance of a single protein in two distinctly different cell types suggests it as the most likely candidate. This coincidence further suggests that tumor cells become resistant by selection of those cells that can express the same gene product as do those normal cells as they undergo immunological commitment.