Oncotarget

Priority Research Papers:

p53 and rapamycin are additive

Barbara Christy, Marco Demaria, Judith Campisi, Jing Huang, Diane Jones, Sherry G. Dodds, Charnae Williams, Gene Hubbard, Carolina B. Livi, Xiaoli Gao, Susan Weintraub, Tyler Curiel, Z. Dave Sharp and Paul Hasty _

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Oncotarget. 2015; 6:15802-15813. https://doi.org/10.18632/oncotarget.4602

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Abstract

Barbara Christy1,5,6,*, Marco Demaria7,*, Judith Campisi7, Jing Huang8, Diane Jones1, Sherry G. Dodds1, Charnae Williams1, Gene Hubbard2, Carolina B. Livi1,9, Xiaoli Gao3, Susan Weintraub3, Tyler Curiel4,5, Z. Dave Sharp1,5,6 and Paul Hasty1,5,6

1 Departments of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

2 Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

3 Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

4 Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

5 Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

6 Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

7 Buck Institute for Research on Aging, Novato, CA, USA

8 Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

9 Current address: Agilent Technologies, Inc., Santa Clara, CA, USA

* These authors have contributed equally to this work

Correspondence to:

Paul Hasty, email:

Keywords: mTOR, p53, rapamycin, longevity, SASP

Received: May 18, 2015 Accepted: June 14, 2015 Published: June 23, 2015

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.


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