Translational infidelity and human cancer: role of the PTI-1 oncogene

Several components of the eukaryotic protein synthesis apparatus have been associated with oncogenic transformation of cells. Altered expression of tr anslation elongation factor 1 alpha (EF-l alpha), a core component of prote in synthesis and closely related sequences have been linked with transforme d phenotypes by several independent studies, in diverse systems. A dominant acting oncogene, prostate tumor inducing gene-1 (PTI-1) has provided furth er evidence for this link. PTI-1 appears to be a hybrid molecule with compo nents derived from both prokaryotic and eukaryotic origins. The predicted p rotein coding moiety represents an EF-IV. molecule. truncated N-terminal to amino acid residue 68 and having six additional point mutations. This codi ng sequence is fused to a 5 ' untranslated legion (UTR) showing strongest h omology to ribosomal RNA derived from Mycoplasma hyopneumoniae. Expression studies using the cloned cDNA in nude mouse tumor formation assays have con firmed the oncogenic nature of the molecule. A broad spectrum of tumor deri ved cell lines, from varied tissue sources and blood samples from patients having confirmed prostate carcinoma, all scored positive for expression of PTI-1, while corresponding normal tissues or blood samples were negative, B ased on its near identity to EF-1 alpha, it is proposed that PTI-1 represen ts a new class of oncogene whose transforming capacity probably arises thro ugh mechanisms including: (i) protein translational infidelity, resulting i n the synthesis of mutant polypeptides due to loss of proofreading function during peptide chain elongation, (ii) by its association with and alterati on of the cytoskeleton, (iii) by impinging on one-particular ol several dif ferent signal transduction pathways through its properties as a G-protein, (C) 1999 Elsevier Science Ltd. All rights reserved.