SIRT1 Inhibits Transforming Growth Factor β-Induced Apoptosis in Glomerular Mesangial Cells via Smad7 Deacetylation

作者：Shinji Kume, Masakazu Haneda, Keizo Kanasaki, Toshiro Sugimoto, Shin‐ichi Araki, Keiji Isshiki, Motohide Isono, Takashi Uzu, Leonard Guarente, Atsunori Kashiwagi, Daisuke Koya · 发表于：Journal of Biological Chemistry · 年份：2006 · DOI：10.1074/jbc.m605904200 · 被引用次数：233 · 研究领域：Histone Deacetylase Inhibitors Research、Sirtuins and Resveratrol in Medicine、Nuclear Receptors and Signaling

SIRT1, a class III histone deacetylase, is considered a key regulator of cell survival and apoptosis through its interaction with nuclear proteins. In this study, we have examined the likelihood and role of the interaction between SIRT1 and Smad7, which mediates transforming growth factor beta (TGFbeta)-induced apoptosis in renal glomerular mesangial cells. Immunoprecipitation analysis revealed that SIRT1 directly interacts with the N terminus of Smad7. Furthermore, SIRT1 reversed acetyl-transferase (p300)-mediated acetylation of two lysine residues (Lys-64 and -70) on Smad7. In mesangial cells, the Smad7 expression level was reduced by SIRT1 overexpression and increased by SIRT1 knockdown. SIRT1-mediated deacetylation of Smad7 enhanced Smad ubiquitination regulatory factor 1 (Smurf1)-mediated ubiquitin proteasome degradation, which contributed to the low expression of Smad7 in SIRT1-overexpressing mesangial cells. Stimulation by TGFbeta or overexpression of Smad7 induced mesangial cell apoptosis, as assessed by morphological apoptotic changes (nuclear condensation) and biological apoptotic markers (cleavages of caspase3 and poly(ADP-ribose) polymerase). However, TGFbeta failed to induce apoptosis in Smad7 knockdown mesangial cells, indicating that Smad7 mainly mediates TGFbeta-induced apoptosis of mesangial cells. Finally, SIRT1 overexpression attenuated both Smad7- and TGFbeta-induced mesangial cell apoptosis, whereas SIRT1 knockdown enhanced this apoptosis. We have conclud...