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.
Highlights
Rapamycin is a naturally occurring antifungal compound produced by bacteria
We provide three lines of evidence that support the notion that p53 and rapamycin are additive
P53 facilitated the ability of rapamycin to suppress the IR-induced senescence-associated secretory phenotype (SASP) in human cells
Summary
Rapamycin is a naturally occurring antifungal compound produced by bacteria. It forms a complex with FKBP12 that allosterically inhibits primarily mTORC1 [1, 2]. mTOR is a serine/threonine kinase found in two complexes, mTORC1 and mTORC2. mTORC1 coordinates cell growth and metabolism in response to environmental stresses, nutrient and energy levels, growth factors and other conditions [3]. Rapamycin extends life span of wild type mice [4], possibly through cancer suppression since mTORC1 signaling is often dysregulated in cancer cells [5]. Rapamycin could have an additive effect with p53 to suppress mTORC1 This possibility is especially important since most cancers are dysfunctional for p53 [32]. Rapamycin extended the life span of p53+/- [10] and p53-/- [11] mice when added to the drinking water or administered in nanoformulated micelles (Rapatar), respectively. These latter results are inconsistent with the notion that p53 regulates mTORC1.
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