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Cyclic Nucleotide Regulation of Plasminogen Activator and Plasminogen Activator-Inhibitor Messenger RNAs in Rat Hepatoma Cells

Departments of Human Genetics and Internal Medicine, University of Michigan Medical School Ann Arbor, Michigan 48109–0618

Address requests for reprints to: Dr. Joanne H. Heaton, Departments of Human Genetics and Internal Medicine, University of Michigan Medical School, Ann Arbor.Michigan 48109-0618.

Abstract

HTC rat hepatoma cells synthesize and secrete tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor type 1 (PAI-1). Incubation with 8-bromo-cAMP increases tPA activity more than 50-fold and, in combination with dexamethasone, causes an additional 4-fold increase. We have investigated the mechanism of the regulation of tPA activity by cyclic nucleotides, both alone and in combination with dexamethasone, by examining the effects of these agents on tPA and PAI-1 mRNA and protein. 8-Bromo-cAMP induces only a 2-fold increase in tPA mRNA and a 5-fold increase in tPA protein which is not sufficient to account for the increase in tPA activity. However, 8-bromo-cAMP causes a 90% decrease in PAI-1 mRNA and a 60–70% decrease in PAI-1 protein, which, taken together with the modest increase in tPA mRNA and protein, can account for the increase in tPA activity. Incubation with 8-bromo-cAMP plus dexamethasone also results in an 80–90% decrease in PAI-1 mRNA, but causes a synergistic 10- to 20-fold increase in tPA mRNA and protein. Regulation of both mRNAs by 8-bromo-cAMP requires concomitant RNA synthesis. Inhibition of protein synthesis by cycloheximide totally blocks the 8-bromo-cAMP-induced decrease in PAI-1 mRNA. Cycloheximide alone causes a 5- to 10-fold increase in tPA mRNA, and no further hormonal effect is observed. Thus, 8-bromo-cAMP increases tPA activity primarily by decreasing PAI-1 mRNA accumulation. The further 4-fold increase caused by 8-bromo-cAMP in the presence of dexamethasone is the result of both a decrease in PAI-1 mRNA and an increase in tPA mRNA. De novo RNA and protein synthesis are required for cAMP regulation of PAI-1 mRNA.

FOOTNOTES

This work was supported by NCI Grant R37-CA-22729.

Received for publication September 22, 1989. Revision received October 20, 1989. Accepted for publication October 20, 1989.

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