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Temporal mTOR inhibition protects Fbxw7-deficient mice from radiation-induced tumor development

Journal Article · · Aging
 [1];  [2];  [2];  [3];  [3];  [3];  [4];  [2]
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division; DOE/OSTI
  2. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division
  3. Univ. of California, San Francisco, CA (United States). Drug Studies Unit
  4. Shandong Univ., Jinan (China). School of Medicine. Dept. of Anatomy; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division
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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 treated Fbxw7+/-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.
Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1627970
Journal Information:
Aging, Journal Name: Aging Journal Issue: 2 Vol. 5; ISSN 1945-4589
Publisher:
Impact JournalsCopyright Statement
Country of Publication:
United States
Language:
English

References (25)

Role of the ubiquitin ligase Fbw7 in cancer progression journal November 2011
The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase journal July 2005
A Nucleolar Isoform of the Fbw7 Ubiquitin Ligase Regulates c-Myc and Cell Size journal October 2004
Exposure to Ionizing Radiation Causes Long-Term Increase in Serum Estradiol and Activation of PI3K-Akt Signaling Pathway in Mouse Mammary Gland journal October 2012
The tumour suppressor C/EBPδ inhibits FBXW7 expression and promotes mammary tumour metastasis journal November 2010
Inactivation of hCDC4 can cause chromosomal instability journal March 2004
Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene journal December 2004
SCFFBW7 regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction journal March 2011
FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation journal February 2008
The evolution of the TOR pathway and its role in cancer journal December 2012
Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7 journal April 2004
Paradoxical suppression of cellular senescence by p53 journal May 2010
Functional Interaction between SEL-10, an F-box Protein, and the Nuclear Form of Activated Notch1 Receptor journal September 2001
The Notch Intracellular Domain Is Ubiquitinated and Negatively Regulated by the Mammalian Sel-10 Homolog journal September 2001
The Fbw7/Human CDC4 Tumor Suppressor Targets Proproliferative Factor KLF5 for Ubiquitination and Degradation through Multiple Phosphodegron Motifs journal June 2010
Fbxw7 contributes to tumor suppression by targeting multiple proteins for ubiquitin-dependent degradation journal August 2006
CDC4 Mutations Occur in a Subset of Colorectal Cancers but Are Not Predicted to Cause Loss of Function and Are Not Associated with Chromosomal Instability journal December 2005
FBXW7/hCDC4 Is a General Tumor Suppressor in Human Cancer journal October 2007
Perifosine Inhibits Mammalian Target of Rapamycin Signaling through Facilitating Degradation of Major Components in the mTOR Axis and Induces Autophagy journal November 2009
The Fbw7 Tumor Suppressor Targets KLF5 for Ubiquitin-Mediated Degradation and Suppresses Breast Cell Proliferation journal May 2010
Pten Regulates Aurora-A and Cooperates with Fbxw7 in Modulating Radiation-Induced Tumor Development journal April 2012
mTOR favors senescence over quiescence in p53-arrested cells journal June 2010
DNA damaging agents and p53 do not cause senescence in quiescent cells, while consecutive re-activation of mTOR is associated with conversion to senescence journal December 2010
Rapamycin extends lifespan and delays tumorigenesis in heterozygous p53+/− mice journal October 2012
Rapalogs in cancer prevention journal December 2012

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TOR-centric view on insulin resistance and diabetic complications: perspective for endocrinologists and gerontologists journal December 2013
FBXW7 Mutations in Patients with Advanced Cancers: Clinical and Molecular Characteristics and Outcomes with mTOR Inhibitors journal February 2014
Latest progress in tyrosine kinase inhibitors journal March 2014
Aberrant regulation of FBW7 in cancer journal March 2014
Targeting Phosphatidylinositide3-Kinase/Akt pathway by BKM120 for radiosensitization in hepatocellular carcinoma journal May 2014
Dietary energy balance modulates ovarian cancer progression and metastasis journal July 2014
Tumor promoter-induced cellular senescence: cell cycle arrest followed by geroconversion journal December 2014
Rejuvenating immunity: “anti-aging drug today” eight years later journal March 2015
Expression profiling reveals transcriptional regulation by Fbxw7/mTOR pathway in radiation-induced mouse thymic lymphomas journal November 2015
Selective anti-cancer agents as anti-aging drugs journal December 2013
Immunosuppressants in cancer prevention and therapy journal December 2013
FBXW7: a critical tumor suppressor of human cancers journal August 2018

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