Driver mutations of the adenoma-carcinoma sequence govern the intestinal epithelial global translational capacity
Wouter L. Smit, Claudia N. Spaan, Ruben J. de Boer, Prashanthi Ramesh, Tânia Martins Garcia, Bartolomeus J. Meijer, Jacqueline Ludovicus Maria Vermeulen, Marco Lezzerini, Alyson W. MacInnes, Jan Köster, Jan Paul Medema, Gijs R. van den Brink, Vanesa Muncan, Jarom Heijmans
Abstract
further enhanced global translation efficiency and was associated with a lower 4E-BP1-to-eIF4E ratio. Quadruple mutant cells with additional P53 loss displayed the highest global translational capacity, paralleled by high proliferation and growth rates, indicating that the proteome is heavily geared toward cell division. Transcriptional reprogramming facilitating global translation included elevated ribogenesis and activation of mTORC1 signaling. Accordingly, interfering with the mTORC1/4E-BP/eIF4E axis inhibited the growth potential endowed by accumulation of multiple drivers. In conclusion, the ACS is characterized by a strongly altered global translational landscape in epithelial cells, exposing a therapeutic potential for direct targeting of the translational apparatus.