Differential regulation of phosphatidylinositol 3-kinase/Akt, mitogen-activated protein kinase, and AMP-activated protein kinase pathways during menadione-induced oxidative stress in the kidney of young and old rats

2004 ◽  
Vol 315 (3) ◽  
pp. 555-561 ◽  
Author(s):  
Quanri Jin ◽  
Bong Sook Jhun ◽  
Suk Hyoung Lee ◽  
Jinhwa Lee ◽  
Yonghao Pi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Kinase ◽  
Differential Regulation ◽  
Mitogen Activated Protein Kinase ◽  
Phosphatidylinositol 3 Kinase ◽  
Mitogen Activated Protein ◽  
Old Rats ◽  
Amp Activated Protein Kinase ◽  
Phosphatidylinositol 3

scholarly journals Proteasome Inactivation Promotes p38 Mitogen-activated Protein Kinase-dependent Phosphatidylinositol 3-kinase Activation and Increases Interleukin-8 Production in Retinal Pigment Epithelial Cells

2009 ◽  
Vol 20 (16) ◽  
pp. 3690-3699 ◽  
Author(s):  
Alexandre F. Fernandes ◽  
Qingning Bian ◽  
Jian-Kang Jiang ◽  
Craig J. Thomas ◽  
Allen Taylor ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Kinase ◽  
Retinal Pigment ◽  
Interleukin 2 ◽  
Mitogen Activated Protein Kinase ◽  
Phosphatidylinositol 3 Kinase ◽  
Oxidative Inactivation ◽  
Sequence Of Events ◽  
Mitogen Activated Protein ◽  
Phosphatidylinositol 3

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.

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