title: Insulin-like growth factor-1 regulates the SIRT1-p53 pathway in cellular senescence.
abstract: Cellular senescence, which is known to halt proliferation of aged and stressed cells, plays a key role against cancer development and is also closely associated with organismal aging. While increased insulin-like growth factor (IGF) signaling induces cell proliferation, survival and cancer progression, disrupted IGF signaling is known to enhance longevity concomitantly with delay in aging processes. The molecular mechanisms involved in the regulation of aging by IGF signaling and whether IGF regulates cellular senescence are still poorly understood. In this study, we demonstrate that IGF-1 exerts a dual function in promoting cell proliferation as well as cellular senescence. While acute IGF-1 exposure promotes cell proliferation and is opposed by p53, prolonged IGF-1 treatment induces premature cellular senescence in a p53-dependent manner. We show that prolonged IGF-1 treatment inhibits SIRT1 deacetylase activity, resulting in increased p53 acetylation as well as p53 stabilization and activation, thus leading to premature cellular senescence. In addition, either expression of SIRT1 or inhibition of p53 prevented IGF-1-induced premature cellular senescence. Together, these findings suggest that p53 acts as a molecular switch in monitoring IGF-1-induced proliferation and premature senescence, and suggest a possible molecular connection involving IGF-1-SIRT1-p53 signaling in cellular senescence and aging.
authors: Department of Biochemistry, Boston University School of Medicine, Boston, MA, 02118, USA.
authors: Duc
authors: D
authors: Tran
authors: Johann
authors: J
authors: Bergholz
authors: Haibo
authors: H
authors: Zhang
authors: Hanbing
authors: H
authors: He
authors: Yang
authors: Y
authors: Wang
authors: Yujun
authors: Y
authors: Zhang
authors: Qintong
authors: Q
authors: Li
authors: James L
authors: JL
authors: Kirkland
authors: Zhi-Xiong
authors: ZX
authors: Xiao
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: IGF-1; SIRT1; aging; p53; senescence