ATTENUATION OF GLUCOCORTICOID RECEPTOR LEVELS BY THE H-RAS ONCOGENE

Certain oncogene products are known to affect the cellular response to glucocorticoids. In particular, glucocorticoid-induced transcription is impaired in H-ras-transformed cells. In this study, we examine the mechanism for this effect in NIH3T3 cells containing stably integrated H-ras genomic sequences. NIH3T3ras cells transfected with the MMTV-CAT reporter exhibit a pronounced reduction in the level of glucocorticoid-induced CAT activity, compared to normal NIH3T3 cells. As the response to glucocorticoids depends on the amount of glucocorticoid receptor protein, we have examined the cellular receptor content in both cell lines. The cytosolic and total cellular GR protein are both markedly lower in NIH3T3ras cells, suggesting that the reduced response is directly due to an attenuation of receptor levels. The steady-state level of glucocorticoid receptor mRNA is appreciably reduced in NIH3T3ras cells, which accounts for the attenuated level of glucocorticoid receptor protein. The rate of glucocorticoid receptor gene transcription is concomitantly decreased in NIH3T3ras cells. The ras effect maps to the proximal promoter of the glucocorticoid receptor gene. These results suggest that a target for activated H-Ras protein may be a transcription factor which partially represses transcription of the glucocorticoid receptor gene.