title: Temporal mTOR inhibition protects Fbxw7-deficient mice from radiation-induced tumor development.
abstract: 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.
authors: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors: Yueyong
authors: Y
authors: Liu
authors: Yurong
authors: Y
authors: Huang
authors: Zeran
authors: Z
authors: Wang
authors: Yong
authors: Y
authors: Huang
authors: Xiaohua
authors: X
authors: Li
authors: Alexander
authors: A
authors: Louie
authors: Guangwei
authors: G
authors: Wei
authors: Jian-Hua
authors: JH
authors: Mao
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D044783:F-Box Proteins / Q000187:drug effects / Q000235:genetics*; D000073979:F-Box-WD Repeat-Containing Protein 7; D016147:Genes, Tumor Suppressor; D051379:Mice; D009154:Mutation; D009381:Neoplasms, Radiation-Induced / Q000188:drug therapy*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000187:drug effects / Q000235:genetics*
chemical_list: D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513272:Fbxw7 protein, mouse; D044767:Ubiquitin-Protein Ligases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus