Oxidative Stress-Induced Inhibition of Sirt1 by Caveolin-1 Promotes p53-Dependent Premature Senescence and Stimulates the Secretion of IL-6 [Developmental Biology]

December 15th, 2014 by Volonte, D., Zou, H., Bartholomew, J. N., Liu, Z., Morel, P. A., Galbiati, F.

Oxidative stress can induce premature cellular senescence (SIPS). Senescent cells secrete various growth factors and cytokines, such as IL-6, that can signal to the tumor microenvironment and promote cancer cell growth. Sirtuin 1 (Sirt1) is a class III histone deacetylase that regulates a variety of physiological processes, including senescence. We found that caveolin-1, a structural protein component of caveolar membranes, is a direct binding partner of Sirt1, as shown by the binding of the scaffolding domain of caveolin-1 (amino acids 82-101) to the caveolin-binding domain (CBD) of Sirt1 (amino acids 310-317). Our data show that oxidative stress promotes the sequestration of Sirt1 into caveolar membranes and the interaction of Sirt1 with caveolin-1, which lead to inhibition of Sirt1 activity. Reactive oxygen species (ROS) stimulation promotes acetylation of p53 and premature senescence in wild type but not caveolin-1 null mouse embryonic fibroblasts (MEFs). Either downregulation of Sirt1 expression or re-expression of caveolin-1 in caveolin-1 null MEFs restores ROS-induced acetylation of p53 and premature senescence. In addition, overexpression of caveolin-1 induces SIPS in p53 wild type but not p53 knockout MEFs. Phosphorylation of caveolin-1 on tyrosine 14 promotes the sequestration of Sirt1 into caveolar membranes and activates the p53/senescence signaling. We also identified IL-6 as a caveolin-1-specific cytokine that is secreted by senescent fibroblasts following the caveolin-1-mediated inhibition of Sirt1. The caveolin-1-mediated secretion of IL-6 by senescent fibroblasts stimulates the growth of cancer cells. Thus, by inhibiting Sirt1, caveolin-1 links free radicals to the activation of the p53/senescence pathway and the pro-tumorigenic properties of IL-6.
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