A mammalian sequence-dependent upstream open reading frame mediates polyamine-regulated translation in yeast

In mammals, control of S-adenosylmethionine decarboxylase (AdoMetDC) transl ation is one component of a feedback network that regulates intracellular l evels of the polyamines, spermidine, and spermine. AdoMetDC mRNA from mamma ls contains a highly conserved upstream open reading frame (uORF) within it s leader sequence that confers polyamine-regulated suppression of translati on on the associated downstream cistron. This regulation is mediated throug h an interaction that depends on the amino acid sequence of the uORF-encode d hexapeptide. It remains to be shown whether polyamines participate direct ly in this interaction or indirectly through a specialized signal transduct ion pathway. We show that Saccharomyces cerevisiae does not have a uORF ass ociated with its AdoMetDC gene (SPE2) and that ribosome loading on the SPE2 mRNA is not positively influenced by polyamine depletion, as it is in mamm alian cells. Nevertheless, the mammalian AdoMetDC uORF, when introduced int o a polyamine auxotroph of yeast, conferred polyamine regulation of both tr anslational efficiency and ribosome loading on the associated mRNA, This re gulatory activity depended on the amino acid sequence encoded by the fourth and fifth codons of the uORF, as in mammalian cells. The fact that the reg ulatory properties of this mammalian translational control element are quit e similar in both mammalian and yeast cells suggests that a specialized sig nal transduction pathway is not required. Rather, it seems likely that poly amines may be directly participating in an interaction between the uORF-enc oded peptide and a constitutive component of the translation machinery, whi ch leads to inhibition of ribosome activity.