POSTTRANSCRIPTIONAL REGULATION OF PRIMATE LDHC MESSENGER-RNA BY ITS AUUUA-LIKE ELEMENTS

The Ldhc locus encodes the testis-specific isozyme of lactate dehydrogenase in mammals. In our efforts to understand the regulatory mechanisms involved in expression of Ldhc, we recognized the possibility that this gene could be posttranscriptionally regulated in certain species as the 3'-untranslated region (3'-UTR) of Ldhc in primates, but not rodents, contains a number of AU-rich motifs and is conserved. To determine whether the primate Ldhc mRNA is posttranscriptionally regulated, comparison of baboon and mouse Ldhc mRNA stability was made in a cell-free system. The results indicated that the baboon mRNA is labile, while that of mouse, which does not contain the AU-rich motifs, is highly stable. Consistent with these results, the steady state level of primate Ldhc was found to be 8 to 12 fold lower than that of the mouse. We show that in a transformed murine germ cell line, the human Ldhc mRNA is moderately unstable, and removal of its 3'-UTR leads to stabilization of the mRNA. Mutations disrupting the AU-rich motifs of human Ldhc result in stabilization of the mRNA in vitro. On the basis of these observations, we conclude that stability of the primate Ldhc transcript is regulated by dispersed AU-rich elements found in its 3'-UTR. Because AU-rich motifs similar to these are found in many mRNAs, these findings may have broad implications.