title: PRAK is essential for ras-induced senescence and tumor suppression.
abstract: Like apoptosis, oncogene-induced senescence is a barrier to tumor development. However, relatively little is known about the signaling pathways mediating the senescence response. p38-regulated/activated protein kinase (PRAK) is a p38 MAPK substrate whose physiological functions are poorly understood. Here we describe a role for PRAK in tumor suppression by demonstrating that PRAK mediates senescence upon activation by p38 in response to oncogenic ras. PRAK deficiency in mice enhances DMBA-induced skin carcinogenesis, coinciding with compromised senescence induction. In primary cells, inactivation of PRAK prevents senescence and promotes oncogenic transformation. Furthermore, we show that PRAK activates p53 by direct phosphorylation. We propose that phosphorylation of p53 by PRAK following activation of p38 MAPK by ras plays an important role in ras-induced senescence and tumor suppression.
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. pqsun@scripps.edu
authors.forename: Peiqing
authors.initials: P
authors.lastname: Sun
authors.forename: Naoto
authors.initials: N
authors.lastname: Yoshizuka
authors.forename: Liguo
authors.initials: L
authors.lastname: New
authors.forename: Bettina A
authors.initials: BA
authors.lastname: Moser
authors.forename: Yilei
authors.initials: Y
authors.lastname: Li
authors.forename: Rong
authors.initials: R
authors.lastname: Liao
authors.forename: Changchuan
authors.initials: C
authors.lastname: Xie
authors.forename: Jianming
authors.initials: J
authors.lastname: Chen
authors.forename: Qingdong
authors.initials: Q
authors.lastname: Deng
authors.forename: Maria
authors.initials: M
authors.lastname: Yamout
authors.forename: Meng-Qiu
authors.initials: MQ
authors.lastname: Dong
authors.forename: Costas G
authors.initials: CG
authors.lastname: Frangou
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.forename: Peter E
authors.initials: PE
authors.lastname: Wright
authors.forename: Jiahuai
authors.initials: J
authors.lastname: Han
mesh_terms: D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C111049:MAP-kinase-activated kinase 5; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins