title: RACK1 antagonizes TNF-α-induced cell death by promoting p38 activation.
abstract: p38 mitogen-activated protein kinase (MAPK) activity has been reported to either promote or suppress cell death, which depends on cell type and stimulus. Our previous report indicates that p38 exerts a protective role in tumor necrosis factor (TNF)-α-induced cell death in L929 fibroblastoma cells. However, key molecules regulating p38 activation remain unclear. Here, we show that ectopic expression of scaffold protein receptor for activated C kinase 1 (RACK1) suppressed TNF-α-induced cell death in L929 cells, which was associated with enhanced p38 activation. Knockdown of endogenous RACK1 expression exhibited opposite effects. The protective role of RACK1 in TNF-α-induced cell death diminished upon blockade of p38 activation. Therefore, RACK1 antagonizes TNF-α-induced cell death through, at least partially, augmenting p38 activation. Further exploration revealed that RACK1 directly bound to MKK3/6 and enhanced the kinase activity of MKK3/6 without affecting MKK3/6 phosphorylation. Similar effects of RACK1 were also observed in primary murine hepatocytes, another cell type sensitive to TNF-α-induced cell death. Taken together, our data suggest that RACK1 is a key factor involved in p38 activation as well as TNF-α-induced cell death.
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, P. R. China.
authors.forename: Qingyang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, P. R. China.
authors.forename: Silei
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, P. R. China.
authors.forename: Jing-Yang
authors.initials: JY
authors.lastname: Wang
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, P. R. China.
authors.forename: Junxia
authors.initials: J
authors.lastname: Cao
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, P. R. China.
authors.forename: Xueying
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, P. R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, P. R. China.
authors.forename: Kun
authors.initials: K
authors.lastname: Han
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, P. R. China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, P. R. China.
authors.forename: Guihua
authors.initials: G
authors.lastname: Qiu
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, P. R. China.
authors.forename: Yawei
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, P. R. China.
authors.forename: Xinying
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, P. R. China.
authors.forename: Chunxia
authors.initials: C
authors.lastname: Qiao
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, P. R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, P. R. China.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Hou
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, P. R. China.
authors.forename: Jiyan
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D018223:Dermatofibrosarcoma / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D048371:MAP Kinase Kinase 3 / Q000378:metabolism; D048669:MAP Kinase Kinase 6 / Q000378:metabolism; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D011485:Protein Binding; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; D009479:Neuropeptides; C419368:RACK1 protein, human; C090294:RACK1 protein, mouse; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; D019204:GTP-Binding Proteins