Zinc inhibits turnover of labile mRNAs in intact cells.
For immediate early genes such as the c-fos proto-oncogene, mRNA breakdown is very rapid and is largely responsible for the transient nature of mRNA accumulation after transcription is stimulated. We found that in several types of cultured cells and in mice, Zn++ caused marked accumulation of c-fos mRNA and that of another labile mRNA, that encoding the tristetraprolin (TTP) protein. Exposure of TK-L cells to 100 microM ZnSO4 caused an increase of c-fos and TTP mRNA levels within 1 h that reached peak levels in 4-8 h and remained constant to 12 h. Increases in fos protein accumulation were also noted. When the cells were exposed to Zn++ for 4 h and then exposed to actinomycin D, both c-fos and TTP mRNA levels remained constant for up to 10 h, indicating that Zn++ was preventing the breakdown of both c-fos and TTP mRNA. Also, 100 microM ZnSO4 inhibited protein synthesis in TK-L cells, suggesting that the effect on mRNA accumulation could have been an indirect effect resulting from inhibited protein synthesis. Zn++ was unable to inhibit the breakdown of TTP and c-fos mRNA in vitro; however, extracts from cells exposed to Zn++ were less able to cause the breakdown of TTP and c-fos mRNAs than were extracts from control cells, again suggesting that Zn++ indirectly affects mRNA stability through inhibition of protein synthesis. These studies suggest that in addition to their effects on gene transcription, Zn++ and other divalent cations may regulate gene expression by affecting mRNA stability.
Howard Hughes Medical Institute Laboratories, Duke University Medical Center, Durham, North Carolina 27710.
G A
GA
Taylor
P J
PJ
Blackshear
D000818:Animals; D002104:Cadmium / Q000494:pharmacology; D004268:DNA-Binding Proteins; D005260:Female; D016762:Genes, fos; D006367:HeLa Cells; D006801:Humans; D017874:Immediate-Early Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D011061:Poly A / Q000378:metabolism; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000378:metabolism*; D051816:Tristetraprolin; D015032:Zinc / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; C000715470:MAS1 protein, human; D011506:Proteins; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D051816:Tristetraprolin; C497552:ZFP36 protein, human; C497553:Zfp36 protein, mouse; D002104:Cadmium; D011061:Poly A; D015032:Zinc