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This Article Full Text Full Text (PDF) All Versions of this Article: 285/2/F258    most recent 00422.2002v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Schroeder, J. M. Articles by Curthoys, N. P. Search for Related Content PubMed PubMed Citation Articles by Schroeder, J. M. Articles by Curthoys, N. P.

pH-responsive stabilization of glutamate dehydrogenase mRNA in LLC-PK₁-F⁺ cells

Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado 80523-1870

Submitted 11 December 2002 ; accepted in final form 4 April 2003

During chronic metabolic acidosis, the adaptive increase in rat renal ammoniagenesis is sustained, in part, by increased expression of mitochondrial glutaminase (GA) and glutamate dehydrogenase (GDH) enzymes. The increase in GA activity results from the pH-responsive stabilization of GA mRNA. The 3'-untranslated region (3'-UTR) of GA mRNA contains a direct repeat of an eight-base AU-rich element (ARE) that binds -crystallin/NADPH:quinone reductase (-crystallin) with high affinity and functions as a pH-response element. RNA EMSAs established that -crystallin also binds to the full-length 3'-UTR of GDH mRNA. This region contains four eight-base sequences that are 88% identical to one of the two GA AREs. Direct binding assays and competition studies indicate that the two individual eight-base AREs from GA mRNA and the four individual GDH sequences bind -crystallin with different affinities. Insertion of the 3'-UTR of GDH cDNA into a -globin expression vector (pG) produced a chimeric mRNA that was stabilized when LLC-PK₁-F⁺ cells were transferred to acidic medium. A pH-responsive stabilization was also observed using a G construct that contained only the single GDH4 ARE and a destabilizing element from phosphoenolpyruvate carboxykinase mRNA. Therefore, during acidosis, the pH-responsive stabilization of GDH mRNA may be accomplished by the same mechanism that affects an increase in GA mRNA.

renal ammoniagenesis; metabolic acidosis; posttranscriptional regulation

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