Novel physiological roles of small uORF-encoded peptides

Genes were transcribed into messenger RNA (mRNA) and encode proteins, which become translated at ribosomes. The encoded proteins are defined as polypeptides of over 100 amino acids in length, permitting them to establish stable folded secondary and defined tertiary structures, whereas smaller peptides have long remained uninvestigated. The mRNA molecules contain the protein-coding region and, in addition, untranslated non-coding regions. Within these noncoding regions are elements that control the translation of the protein-coding region. In a number of proteins, the upstream untranslated regions (5 -UTRs) contain short coding sequences that may encode small peptides. It is generally assumed that these small upstream open reading frames (uORFs) serve to regulate the translation of the mRNA-encoded proteins and that the encoded small peptides do not have any independent physiological function. However, strikingly, the amino acid sequence of some uORF-encoded peptides are evolutionary highly conserved. This might indicate that these peptides fulfill additional and potentially independent physiological functions beyond translational control. We aim therefore to investigate if a highly conserved uORF-encoded peptide encoded within the p27Kip1 mRNA has an additional biological function beyond translational control. In order to investigate potential roles of the short hydrophobic peptide encoded by this uORF, we aim to establish techniques that permit a functional analysis of these peptides. This project may uncover a novel class of small bioactive peptides.