title: p53 and rapamycin are additive.
abstract: Mechanistic target of rapamycin (mTOR) is a kinase found in a complex (mTORC1) that enables macromolecular synthesis and cell growth and is implicated in cancer etiology. The rapamycin-FK506 binding protein 12 (FKBP12) complex allosterically inhibits mTORC1. In response to stress, p53 inhibits mTORC1 through a separate pathway involving cell signaling and amino acid sensing. Thus, these different mechanisms could be additive. Here we show that p53 improved the ability of rapamycin to: 1) extend mouse life span, 2) suppress ionizing radiation (IR)-induced senescence-associated secretory phenotype (SASP) and 3) increase the levels of amino acids and citric acid in mouse embryonic stem (ES) cells. This additive effect could have implications for cancer treatment since rapamycin and p53 are anti-oncogenic.
authors.affiliation: Departments of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Christy
authors.affiliation: Buck Institute for Research on Aging, Novato, CA, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Demaria
authors.affiliation: Buck Institute for Research on Aging, Novato, CA, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Campisi
authors.affiliation: Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.affiliation: Departments of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Jones
authors.affiliation: Departments of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Sherry G
authors.initials: SG
authors.lastname: Dodds
authors.affiliation: Departments of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Charnae
authors.initials: C
authors.lastname: Williams
authors.affiliation: Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Gene
authors.initials: G
authors.lastname: Hubbard
authors.affiliation: Departments of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Current address: Agilent Technologies, Inc., Santa Clara, CA, USA.
authors.forename: Carolina B
authors.initials: CB
authors.lastname: Livi
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Weintraub
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Curiel
authors.affiliation: Departments of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Z Dave
authors.initials: ZD
authors.lastname: Sharp
authors.affiliation: Departments of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Hasty
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005347:Fibroblasts; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015398:Signal Transduction; D020123:Sirolimus / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: SASP; longevity; mTOR; p53; rapamycin