Translational Derepression and Oncogene Expression in Breast Cancer Cells
Breast Cancer Cells
Drs. Anuradha Mehta, Christopher Trotta and Stuart Peltz (PTC Therapeutics) have uncovered a novel mechanism whereby the translation efficiency of oncogenes is increased in cancer cells.
The human epidermal growth factor receptor 2 (Her-2) is an established oncogene whose overexpression drives metastasis in about 25% of breast cancer patients. In the April 15th issue of Genes & Development, the researchers report that an element within the 3' untranslated region (UTR) of Her2 mRNA can inhibit translational repression by the 5' upstream open reading frame (uORF), and thereby increase Her2 translation in breast cancer cells.
Like a subset of eukaryotic genes that are important regulators of gene expression, the 5'UTR of Her-2 encodes a uORF that interferes with efficient translation by the ribosome, keeping Her-2 protein levels low in normal cells. Dr. Mehta and colleagues now show that the 3' UTR overrides the inhibitory effects of the 5' UTR in Her2-positive breast cancer cells but does not function in cells that don't express high levels of Her2 protein. The scientists identified a sequence within the 3' UTR - the 'Translation Derepression Element" (TDE) - which functions as a docking site for RNA-binding proteins to block 5' UTR-mediated translation repression, and effectively increases Her2 translation efficiency in cancerous cells.
"These results underscore the importance of post-transcriptional control processes in regulating gene expression," cCommented Stuart Peltz, Ph.D. President and CEO of PTC Therapeutics. "The understanding of these mechanisms is important for the identification of new molecular targets for drug-discovery to treat cancer."