期刊
CELLULAR SIGNALLING
卷 19, 期 7, 页码 1583-1595出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2007.02.005
关键词
angiotensin II; protein degradation; insulin-like growth factor-I; protein kinase C; protein kinase R; NF-kappa B
类别
Insulin-like growth factor-I (IGF-I) has been shown to attenuate protein degradation in murine myotubes induced by angiotensin II through downregulation of the ubiquitin-proteasome pathway, although the mechanism is not known. Angiotensin II is known to upregulate this pathway through a cellular signalling mechanism involving release of arachidonic acid, activation of protein kinase C alpha (PKC alpha), degradation of inhibitor-kappa B kappa B (I-kappa KB) and nuclear migration of nuclear factor-kappa B (NF-kappa B), and all of these events were attenuated by IGF-I (13.2 nM). Induction of the ubiquitin-proteasome pathway has been linked to activation of the RNA-activated protein kinase (PKR), since an inhibitor of PKR attenuated proteasome expression and activity in response to angiotensin II and prevented the decrease in the myofibrillar protein myosin. Angiotensin II induced phosphorylation of PKR and of the eukaryotic initiation factor-2 (eIF2) on the alpha-subunit, and this was attenuated by IGF-I, by induction of the expression of protein phosphatase I, which dephosphorylates PKR. Release of arachidonic acid and activation of PKC alpha by angiotensin II were attenuated by an inhibitor of PKR and IGF-I, and the effect was reversed by Salubrinal (15 mu M), an inhibitor of eIF2 alpha dephosphorylation, as was activation of PKC alpha. In addition myotubes transfected with a dominant-negative PKR (PKR Delta 6) showed no release of arachidonate in response to Ang II, and no activation of PKC alpha. These results suggest that phosphorylation of PKR by angiotensin II was responsible for the activation of the PLA(2)/PKC pathway leading to activation of NF-kappa B and that IGF-I attenuates protein degradation due to an inhibitory effect on activation of PKR. (c) 2007 Elsevier Inc. All rights reserved.
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