A profusion of upstream open reading frame mechanisms in polyamine-responsive translational regulation

Abstract

In many eukaryotic mRNAs one or more short 'upstream' open reading frames, uORFs, precede the initiator of the main coding sequence. Upstream ORFs are functionally diverse as illustrated by their variety of features in polyamine pathway biosynthetic mRNAs. Their propensity to act as sensors for regulatory circuits and to amplify the signals likely explains their occurrence in most polyamine pathway mRNAs. The uORF-mediated polyamine responsive autoregulatory circuits found in polyamine pathway mRNAs exemplify the translationally regulated dynamic interface between components of the proteome and metabolism.

Figure 1.

Schematic models for the effect of upstream initiation on initiation downstream. (A) Schematic representation of mRNA with an upstream and a downstream initiation sites. (B) Relationship between increasing initiation efficiency and fractional utilization of each initiation codon. (C) Schematic models for the role of uORFs in regulating the expression of various mRNAs encoding proteins in the polyamine biosynthetic pathway.

Figure 2.

Cartoon representation of the biosynthesis of polyamines in vertebrate cells and the accompanying translational regulation through upstream open reading frames. The mRNA structure for the catabolic enzyme SSAT which features in vertebrates an uORF that overlaps the main coding sequence and in many cases a discrete uORF further 5′, is not shown. ODC, ornithine decarboxylase; OAZ, ornithine decarboxylase antizyme; AZI, antizyme inhibitor; AdoMetDC, S-adenosylmethionine decarboxylase; SpmSym, spermine synthase.