Rpl24Bst mutation suppresses colorectal cancer by promoting eEF2 phosphorylation via eEF2K

eLife

William Liam Faller¹  John RP Knight¹  Nikola Vlahov¹  Rachel A Ridgway¹  David M Gay²  Owen J Sansom²  Christopher Proud³  Anne E Willis⁴  Christopher Mark Smales⁵  Tobias von der Haar⁵  Giovanna R Mallucci⁶ 

[1] CRUK Beatson Institute, Garscube Estate, Glasgow, United Kingdom;CRUK Beatson Institute, Garscube Estate, Glasgow, United Kingdom;Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom;Department of Biological Sciences, University of Adelaide, Adelaide, Australia;Lifelong Health, South Australian Health and Medical Research Institute, Adelaide, Australia;MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom;School of Biosciences, Division of Natural Sciences, University of Kent, Kent, United Kingdom;UK Dementia Research Institute at the University of Cambridge and Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom;

关键词: translation;    protein sythesis;    intestinal cancer;    in vivo models;    RPL24;    eEF2K;    Mouse;   

DOI  :  10.7554/eLife.69729

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Increased protein synthesis supports the rapid cell proliferation associated with cancer. The Rpl24Bst mutant mouse reduces the expression of the ribosomal protein RPL24 and has been used to suppress translation and limit tumorigenesis in multiple mouse models of cancer. Here, we show that Rpl24Bst also suppresses tumorigenesis and proliferation in a model of colorectal cancer (CRC) with two common patient mutations, Apc and Kras. In contrast to previous reports, Rpl24Bst mutation has no effect on ribosomal subunit abundance but suppresses translation elongation through phosphorylation of eEF2, reducing protein synthesis by 40% in tumour cells. Ablating eEF2 phosphorylation in Rpl24Bst mutant mice by inactivating its kinase, eEF2K, completely restores the rates of elongation and protein synthesis. Furthermore, eEF2K activity is required for the Rpl24Bst mutant to suppress tumorigenesis. This work demonstrates that elevation of eEF2 phosphorylation is an effective means to suppress colorectal tumorigenesis with two driver mutations. This positions translation elongation as a therapeutic target in CRC, as well as in other cancers where the Rpl24Bst mutation has a tumour suppressive effect in mouse models.

【 授权许可】

CC BY