THE UPSTREAM OPEN READING FRAME OF THE MESSENGER-RNA ENCODING S-ADENOSYLMETHIONINE DECARBOXYLASE IS A POLYAMINE-RESPONSIVE TRANSLATIONAL CONTROL ELEMENT

S-Adenosylmethionine decarboxylase (AdoMetDC) is a key enzyme in the p athway of polyamine biosynthesis. The cellular levels of the polyamine s specifically regulate AdoMetDC translation through the 5'-leader of the mRNA, which contains a small upstream open reading frame (uORF) 14 nucleotides from the cap. Mutating the initiation codon of the uORF, which encodes a peptide product with the sequence MAGDIS, abolished re gula tion, In addition, the uORF is sufficient, by itself, to provide polyamine regulation when inserted into the 5'-leader of the human gro wth hormone mRNA. Changing the amino acid sequence at the carboxyl ter minus of the peptide product of the uORF abolished polyamine regulatio n. In contrast, altering the nucleotide sequence of the uORF at degene rate positions, without changing the amino acid sequence of the peptid e, did not affect regulation. Extending the distance between cap and u ORF, thereby changing the rate of initiation at the initiator AUG of t he uORF, did not alter polyamine regulation. When the uORF was extende d so as to overlap, out of frame, the downstream major cistron, polyam ine regulation was abolished, We propose that polyamines do not modula te the rate of recognition of the uORF but rather regulate interaction of the peptide product of the uORF with its target.