A Posttranslational Modification Cascade Involving p38, Tip60, and PRAK Mediates Oncogene-Induced Senescence

详细信息    查看全文

• 作者：Hui Zheng¹ ; ³ ; Alim Seit-Nebi¹ ; ³ ; ⁴ ; Xuemei Han² ; Aaron Aslanian² ; John Tat¹ ; Rong Liao¹ ; John R. Yates III² ; Peiqing Sun¹ ; ^{pqsun@scripps.edu}
• 刊名：Molecular Cell
• 出版年：2013
• 出版时间：6 June, 2013
• 年：2013
• 卷：50
• 期：5
• 页码：699-710
• 全文大小：2737 K

文摘

| Figures/TablesFigures/Tables | ReferencesReferences

Summary

Oncogene-induced senescence is an important tumor-suppressing defense mechanism. However, relatively little is known about the signaling pathway mediating the senescence response. Here, we demonstrate that a multifunctional acetyltransferase, Tip60, plays an essential role in oncogenic ras-induced senescence. Further investigation reveals a cascade of posttranslational modifications involving p38, Tip60, and PRAK, three proteins that are essential for ras-induced senescence. Upon activation by ras, p38 induces the acetyltransferase activity of Tip60 through phosphorylation of Thr158; activated Tip60 in turn directly interacts with and induces the protein kinase activity of PRAK through acetylation of K364 in a manner that depends on phosphorylation of both Tip60 and PRAK by p38. These posttranslational modifications are critical for the prosenescent function of Tip60 and PRAK, respectively. These results have defined a signaling pathway that mediates oncogene-induced senescence, and identified posttranslational modifications that regulate the enzymatic activity and biological functions of Tip60 and PRAK.