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Proteasome Inactivation Promotes p38 MAPK‐Dependent PI3K Activation and Increases IL‐8 Production
Author(s) -
Shang Fu,
Fernandes Alexandre F,
Bian Qingning,
Taylor Allen,
Pereira Paulo
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.530.6
Subject(s) - proteasome , protein kinase b , microbiology and biotechnology , p38 mitogen activated protein kinases , pi3k/akt/mtor pathway , chemistry , mapk/erk pathway , oxidative stress , signal transduction , phosphorylation , downregulation and upregulation , biology , biochemistry , gene
Oxidative stress and inflammation are implicated in the pathogenesis of many age‐related diseases. The objective of this work is to elucidate the molecular link between oxidative stress and expression of pro‐inflammatory cytokines. We demonstrated that oxidative inactivation of the proteasome is a molecular link between oxidative stress and over‐expression of IL‐8. We also elucidated a novel molecular mechanism underlying the upregulation of IL‐8 induced by proteasome inactivation. Proteasome inactivation in retinal pigment epithelial cells resulted in activation of p38 MAPK, EGFR and PI3Ksignaling pathways, and a dramatic increase in the expression of IL‐8. Blocking any of these signaling pathways abolished the proteasome‐inactivation‐induced production of IL‐8. Using chemical inhibitors and constitutively active and mutant forms of MKK3, MKK6 and Akt, we elucidated a cascade of sequential activation of these signaling pathways in response to proteasome inactivation. The sequential events of this cascade are: proteasome inactivation, activation of MKK3/MKK6, activation of p38 MAPK, EGFR phosphorylation, PI3K activation and increased IL‐8 expression. Proteasome inactivation also induced a sustained Akt activation, but inhibition of Akt activity did not block proteasome‐inactivation‐induced IL‐8 production. Together, these data elucidate a novel cross‐talk of signaling pathways that lead to increased IL‐8 production in response to proteasome inactivation.