TY - JOUR T1 - Temporal mTOR inhibition protects Fbxw7-deficient mice from radiation-induced tumor development. JF - Aging (Albany NY) Y1 - 2013 A1 - Liu, Yueyong A1 - Huang, Yurong A1 - Wang, Zeran A1 - Huang, Yong A1 - Li, Xiaohua A1 - Louie, Alexander A1 - Wei, Guangwei A1 - Jiang-Hua Mao KW - Animals KW - Cell Transformation, Neoplastic KW - F-Box Proteins KW - Genes, Tumor Suppressor KW - Mice KW - Mutation KW - Neoplasms, Radiation-Induced KW - Signal Transduction KW - Sirolimus KW - TOR Serine-Threonine Kinases KW - Ubiquitin-Protein Ligases AB -

FBXW7 acts as a tumor suppressor in numerous types of human cancers through ubiquitination of different oncoproteins including mTOR. However, how the mutation/loss of Fbxw7 results in tumor development remains largely unknown. Here we report that downregulation of mTOR by radiation is Fbxw7-dependent, and short-term mTOR inhibition by rapamycin after exposure to radiation significantly postpones tumor development in Fbxw7/p53 double heterozygous (Fbxw7+/-p53+/-) mice but not in p53 single heterozygous (p53+/-) mice. Tumor latency of rapamycin treated Fbxw7+/-p53+/- mice is remarkably similar to those of p53+/- mice while placebo treatedFbxw7+/-p53+/- mice develop tumor significantly earlier than placebo treated p53+/- mice. Furthermore, we surprisingly find that, although temporal treatment of rapamycin is given at a young age, the inhibition of mTOR activity sustainably remains in tumors. These results indicate that inhibition of mTOR signaling pathway suppresses the contribution of Fbxw7 loss toward tumor development.

VL - 5 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23454868?dopt=Abstract ER -