title: Induction of p38δ expression plays an essential role in oncogenic ras-induced senescence.
abstract: Oncogene-induced senescence is a stable proliferative arrest that serves as a tumor-suppressing defense mechanism. p38 mitogen-activated protein kinase (MAPK) has been implicated in oncogene-induced senescence and tumor suppression. However, the specific role of each of the four p38 isoforms in oncogene-induced senescence is not fully understood. Here, we demonstrate that p38δ mediates oncogene-induced senescence through a p53- and p16(INK4A)-independent mechanism. Instead, evidence suggests a link between p38δ and the DNA damage pathways. Moreover, we have discovered a novel mechanism that enhances the expression of p38δ during senescence. In this mechanism, oncogenic ras induces the Raf-1-MEK-extracellular signal-regulated kinase (ERK) pathway, which, in turn, activates the AP-1 and Ets transcription factors that are bound to the p38δ promoter, leading to increased transcription of p38δ. These findings indicate that induction of the prosenescent function of p38δ by oncogenic ras is achieved through 2 mechanisms, transcriptional activation by the Raf-1-MEK-ERK-AP-1/Ets pathway, which increases the cellular concentration of the p38δ protein, and posttranslational modification by MKK3/6, which stimulates the enzymatic activity of p38δ. In addition, these studies identify the AP-1 and Ets transcription factors as novel signaling components in the senescence-inducing pathway.
authors.affiliation: Department of Cell and Molecular Biology.
authors.forename: Jinny
authors.initials: J
authors.lastname: Kwong
authors.forename: Michelle
authors.initials: M
authors.lastname: Chen
authors.forename: Dan
authors.initials: D
authors.lastname: Lv
authors.forename: Na
authors.initials: N
authors.lastname: Luo
authors.forename: Weijun
authors.initials: W
authors.lastname: Su
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
authors.forename: Peiqing
authors.initials: P
authors.lastname: Sun
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D048371:MAP Kinase Kinase 3 / Q000235:genetics / Q000378:metabolism; D048669:MAP Kinase Kinase 6 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D048292:Mitogen-Activated Protein Kinase 13 / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D050784:Proto-Oncogene Protein c-ets-1; D018808:Transcription Factor AP-1; D016159:Tumor Suppressor Protein p53; D048292:Mitogen-Activated Protein Kinase 13; D019908:Proto-Oncogene Proteins c-raf; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; D018631:ras Proteins