Glucocorticoid inhibition of gene expression and proliferation of murine lymphoid cells in vitro.
Glucocorticoids inhibit the proliferation of murine T-lymphoma P1798 cells. P1798 cells do not die in the presence of dexamethasone, and the process of inhibition of proliferation is completely reversible. As cells cease to divide, expression of a number of genes is inhibited. Among these are genes the expression of which is regulated in some manner that is linked to cell proliferation. We have undertaken to study the mechanism whereby glucocorticoids inhibit the expression of genes in P1798 cells. Three model systems will be reviewed. In all cases, these appear to be examples of secondary regulation. Glucocorticoid-mediated inhibition of transcription of the DNA encoding ribosomal RNA (rDNA) has been investigated in some detail. The data indicate that dexamethasone causes a decrease in the amount or activity of an RNA polymerase I transcription initiation factor. This factor exhibits a short biological half-life and the data are consistent with the hypothesis that glucocorticoids regulate the synthesis of this transcription factor. The gene encoding thymidine kinase appears to be regulated in a similar fashion. On this basis, we propose that glucocorticoids may have the general property of regulating the synthesis of certain transcription factors. Glucocorticoids also regulate the translation of a certain class of mRNAs, including those that encode ribosomal proteins. These are characterized by a low efficiency of translation in untreated cells. Upon exposure to dexamethasone, the translation of these mRNAs is disproportionately inhibited. We speculate that translation of the mRNAs encoding certain transcription factors may be regulated in a similar fashion. Specifically, we propose that transcription of certain proliferation-related genes may be dependent upon factors of short biological half-life. These are encoded by mRNAs that are poorly translated under optimal growth conditions. Any slight perturbation in translation efficiency, as caused by glucocorticoids, results in a disproportionate inhibition of synthesis of these hypothetical transcription factors. Transcription of a class of proliferation-related genes ceases as a result.
Thompson
E A
EA
Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston 77550.
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004275:DNA, Ribosomal / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology*; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D013937:Thymidine Kinase / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D004275:DNA, Ribosomal; D005938:Glucocorticoids; D012333:RNA, Messenger; D013937:Thymidine Kinase