Insulin-like growth factor-1 regulates the SIRT1-p53 pathway in cellular senescence

Authors

  • Duc Tran,

    1. Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA
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  • Johann Bergholz,

    1. Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, 610014, China
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  • Haibo Zhang,

    1. Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, 610014, China
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  • Hanbing He,

    1. Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, 610014, China
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  • Yang Wang,

    1. Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, 610014, China
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  • Yujun Zhang,

    1. Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, 610014, China
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  • Qintong Li,

    1. Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, 610014, China
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  • James L. Kirkland,

    1. Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, MN, USA
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  • Zhi-Xiong Xiao

    Corresponding author
    1. Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, 610014, China
    • Correspondence

      Zhi-Xiong Xiao, Center of Growth, Metabolism and Aging, College of Life Sciences and State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610014, China. Tel.: +86 8541 5509; fax: +86 8541 5509; e-mail: jimzx@scu.edu.cn

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Summary

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.

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