Ribosomal protein eL42 contributes to the catalytic activity of the yeast ribosome at the elongation step of translation

In Vitro Analysis of Protein:Protein Interactions in the Human Cancer-Pertinent rp.eL42-p53-Mdm2 Pathway

“…At this stage, one can wonder if the only role of the overexpression of eL42 as a cancer promoter is the downregulation of p53. However, the following previous observations strongly support another role for the overexpression of eL42 in cancer cells: (i) in the crystallographic structure of S. cerevisiae 80S ribosome or of the 50S subunit of Haloarcula marismortui (Hma), cycloheximide, an antibiotic of the glutarimide family, and a strong inhibitor of translation in eukaryotic cells, had been shown to target the eL42 protein and to make contact with the lysyl residue (Lys-55 in S. cerevisiae and Lys-51 in Hma) [13]. This result argues for a critical role for this lysyl residue at the PTC of the eukaryal or the archaebacterial ribosomes; (ii) in addition, several yeast strains are known to exhibit resistance mutations among which is the P56Q mutation in eL42 that renders them resistant to cycloheximide [13].…”

“…However, the following previous observations strongly support another role for the overexpression of eL42 in cancer cells: (i) in the crystallographic structure of S. cerevisiae 80S ribosome or of the 50S subunit of Haloarcula marismortui (Hma), cycloheximide, an antibiotic of the glutarimide family, and a strong inhibitor of translation in eukaryotic cells, had been shown to target the eL42 protein and to make contact with the lysyl residue (Lys-55 in S. cerevisiae and Lys-51 in Hma) [13]. This result argues for a critical role for this lysyl residue at the PTC of the eukaryal or the archaebacterial ribosomes; (ii) in addition, several yeast strains are known to exhibit resistance mutations among which is the P56Q mutation in eL42 that renders them resistant to cycloheximide [13]. The fact that cycloheximide inhibits protein biosynthesis by binding to Lys-55 of eL42, while the mutation P56Q renders some yeast strains resistant to cycloheximide, indicates that these two adjacent amino acid residues (Lys-55 and Pro-56) are involved in the binding and in the inhibitory effect of cycloheximide on the activity of the ribosome; (iii) moreover, in a previous study on S. pombe cells [33], have demonstrated that the protein Set13 is a specific methyltransferase responsible for monomethylation at lysine 55 in rp eL42.…”

“…Another explanation for the overexpression of eL42 in cancer is that this rp essential for the elongation step of translation [13] could be overproduced to enhance the rate of the translation process in order to sustain the capacity of hyperproliferation of cancer cells. Thus, in addition to its extraribosomal role, the overexpression of eL42 would be favourable to cancer promotion in line with its ribosomal role in increasing the rate of translation elongation [13]. This proposition is consistent with the demonstration that Lys-55 residue of yeast eL42 was recently shown to be involved in the catalysis of peptide bond formation at the peptidyl transferase center of S. pombe ribosomes [13].…”

“…Thus, in addition to its extraribosomal role, the overexpression of eL42 would be favourable to cancer promotion in line with its ribosomal role in increasing the rate of translation elongation [13]. This proposition is consistent with the demonstration that Lys-55 residue of yeast eL42 was recently shown to be involved in the catalysis of peptide bond formation at the peptidyl transferase center of S. pombe ribosomes [13]. We addressed the question of an eventual ribosomal role of eL42 overexpression on the increase of the rate of translation elongation by measuring the poly(U)-dependent poly(Phe) synthesis activity of human 80S ribosomes in the presence of purified human recombinant eL42.…”

“…One of these rps is the eukaryote-specific large subunit ribosomal protein eL42 (formerly L42A or L42AB in yeast, L36a or L36a-like in human, or L44e in archaea). The ribosomal protein eL42 (rp eL42) presents the following characteristics: (i) it was recently shown to directly and actively contribute to the activity of 80S ribosomes at the elongation step of translation [13], thus suggesting that this rp might control the rate of protein biosynthesis in health and in disease; (ii) it was found to be overexpressed in human hepatocellular carcinoma as well as in several human tumor cell-lines, suggesting that its extraribosomal role might be related to tumor cell proliferation [14]; (iii) in the crystallographic structure of S. cerevisiae 80S ribosomes or of the 50S subunit of Haloarcula marismortui, most of the anticancer drugs were shown to target the eL42 protein [15 -19]. These observations point out a connection between protein synthesis on the ribosome and cancer cells growth.…”