title: A posttranslational modification cascade involving p38, Tip60, and PRAK mediates oncogene-induced senescence.
abstract: 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.
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.forename: Alim
authors.initials: A
authors.lastname: Seit-Nebi
authors.forename: Xuemei
authors.initials: X
authors.lastname: Han
authors.forename: Aaron
authors.initials: A
authors.lastname: Aslanian
authors.forename: John
authors.initials: J
authors.lastname: Tat
authors.forename: Rong
authors.initials: R
authors.lastname: Liao
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.forename: Peiqing
authors.initials: P
authors.lastname: Sun
mesh_terms: D000107:Acetylation; D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics*; D011905:Genes, ras; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000074443:Lysine Acetyltransferase 5; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013912:Threonine / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D013912:Threonine; C111049:MAP-kinase-activated kinase 5; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases