Glucocorticoid regulation of G1 cyclin-dependent kinase genes in lymphoid cells

K. Rhee, D. Reisman, W. Bresnahan, E. A. Thompson

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

These experiments were undertaken to study cell cycle-dependent regulation of expression of genes encoding cyclin-dependent kinases (Cdks). P1798 T- lymphoma cells were studied as a model system, since these cells undergo reversible G0 arrest within 24 h after addition of 0.1 μM dexamethasone to mid log phase cultures. G0 arrest is associated with inhibition of expression of several Cdks. The mRNAs encoding Cdk1 and Cdk4 decreased by 80- 90% within 24 h. Fifty % inhibition of Cdk4 mRNA occurred within about 4 h, and 50% inhibition of Cdk1 mRNA was observed within 12-14 h. There was a slight decrease (<50%) in the abundance of the mRNAs encoding Cdk2 and Cdk5. Cdk6 mRNA did not decrease in glucocorticoid-treated cells. Cdk1 and Cdk2 protein levels were reduced by no more than 50-70% within 24 h after the addition of dexamethasone, and the amounts of Cdk5 and Cdk6 protein did not change. However, the amount of Cdk4 protein decreased by >90% under these circumstances. P1798 cells enter S phase in a synchronous fashion within 16- 20 h after removal of dexamethasone. Cdk1, Cdk2, and Cdk5 mRNAs and proteins increased at or after the time that cells began to enter S phase. The mRNA encoding Cdk4 increased much more rapidly after removal of glucocorticoids, and a 5-fold increase in Cdk4 mRNA abundance was observed within 8 h after removal of the steroid. A corresponding increase in Cdk4 protein was observed, indicating that inhibition of Cdk4 expression is more proximal to the glucocorticoid-induced blockade in G1 progression. Glucocorticoids also inhibited Cdk4 expression in cells that were arrested at the G1 S boundary by thymidine block, but expression of Cdk1 was not inhibited in such cells. This observation indicates that glucocorticoid regulation of Cdk4 is not dependent on cell cycle progression, whereas inhibition of Cdk1 is probably secondary to G0 arrest. Nuclear run-on data indicate that dexamethasone inhibits transcription of Cdk4 in P1798 cells. Furthermore, glucocorticoids inhibited expression of Cdk4 in activated splenocytes, with no significant effect on Cdk6 expression. Glucocorticoids regulate expression of several G1 cyclin-dependent kinase genes. Some of these (such as Cdk1) are inhibited as cells withdraw into G0. Cdk4 appears to be directly regulated by glucocorticoids, and inhibition of this G1 cyclin-dependent kinase may play a role in glucocorticoid-mediated G0 arrest of lymphoid cells.

Original languageEnglish (US)
Pages (from-to)691-698
Number of pages8
JournalCell Growth and Differentiation
Volume6
Issue number6
StatePublished - 1995

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