{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T21:52:28Z","timestamp":1761947548526},"reference-count":69,"publisher":"American Society for Cell Biology (ASCB)","issue":"16","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["MBoC"],"published-print":{"date-parts":[[2009,8,15]]},"abstract":"<jats:p>Oxidative stress and inflammation are implicated in the pathogenesis of many age-related diseases. We have demonstrated previously that oxidative inactivation of the proteasome is a molecular link between oxidative stress and overexpression of interleukin (IL)-8. Here, we elucidated a novel signaling cascade that leads to up-regulation of IL-8 in response to proteasome inactivation. The sequence of events in this cascade includes proteasome inactivation, activation of mitogen-activated protein kinase kinase (MKK)3\/MKK6, activation of p38 mitogen-activated protein kinase (MAPK), epidermal growth factor receptor phosphorylation, phosphatidylinositol 3-kinase (PI3K) activation and increased IL-8 expression. Blocking any of these signaling pathways abolished the up-regulation of IL-8 induced by proteasome inhibition. Although Akt is also activated in response to proteasome inactivation, we found that the PI3K-dependent up-regulation of IL-8 is independent of 3-phosphoinositide-dependent protein kinase (PDK)1 and Akt. Inhibition of PDK1 and Akt with chemical inhibitors or expression of constitutive active Akt had little effects on IL-8 expression in response to proteasome inactivation. In contrast, inhibition of interleukin 2-inducible T cell kinase, a kinase downstream of PI3K, significantly reduced the expression and secretion of IL-8 in response to proteasome inactivation. Together, these data elucidate a novel signaling network that leads to increased IL-8 production in response to proteasome inactivation.<\/jats:p>","DOI":"10.1091\/mbc.e08-10-1068","type":"journal-article","created":{"date-parts":[[2009,7,2]],"date-time":"2009-07-02T01:10:37Z","timestamp":1246497037000},"page":"3690-3699","source":"Crossref","is-referenced-by-count":27,"title":["Proteasome Inactivation Promotes p38 Mitogen-activated Protein Kinase-dependent Phosphatidylinositol 3-kinase Activation and Increases Interleukin-8 Production in Retinal Pigment Epithelial Cells"],"prefix":"10.1091","volume":"20","author":[{"given":"Alexandre F.","family":"Fernandes","sequence":"first","affiliation":[{"name":"*Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111;"},{"name":"Centre of Ophthalmology, Institute of Biomedical Research on Light and Image\u2013Faculty of Medicine, University of Coimbra, 3004-548 Coimbra, Portugal; and"}]},{"given":"Qingning","family":"Bian","sequence":"additional","affiliation":[{"name":"*Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111;"}]},{"given":"Jian-Kang","family":"Jiang","sequence":"additional","affiliation":[{"name":"Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-3370"}]},{"given":"Craig J.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-3370"}]},{"given":"Allen","family":"Taylor","sequence":"additional","affiliation":[{"name":"*Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111;"}]},{"given":"Paulo","family":"Pereira","sequence":"additional","affiliation":[{"name":"Centre of Ophthalmology, Institute of Biomedical Research on Light and Image\u2013Faculty of Medicine, University of Coimbra, 3004-548 Coimbra, Portugal; and"}]},{"given":"Fu","family":"Shang","sequence":"additional","affiliation":[{"name":"*Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111;"}]}],"member":"1076","reference":[{"key":"B1","doi-asserted-by":"crossref","first-page":"3214","DOI":"10.1038\/sj.onc.1210413","volume":"26","author":"Adhikari A.","year":"2007","journal-title":"Oncogene"},{"key":"B2","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1158\/1541-7786.MCR-04-0065","volume":"3","author":"Bachelor M. 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