Genetic deletion of PKR abrogates TNF-induced activation of IκBα kinase, JNK, Akt and cell proliferation but potentiates p44/p42 MAPK and p38 MAPK activation

被引:85
作者
Takada, Y.
Ichikawa, H.
Pataer, A.
Swisher, S.
Aggarwal, B. B.
机构
[1] Univ Texas, MD Anderson Canc Ctr, Dept Expt Therapeut, Cytokine Res Lab, Houston, TX 77030 USA
[2] Univ Texas, MD Anderson Canc Ctr, Dept Thorac & Cardiovasc Surg, Houston, TX 77030 USA
关键词
PKR; Akt; MAPK; JNK; NF-kappa B; TNF; survival; apoptosis;
D O I
10.1038/sj.onc.1209906
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Double-stranded RNA-dependent protein kinase (PKR), a ubiquitously expressed serine/threonine kinase, has been implicated in the regulation or modulation of cell growth through multiple signaling pathways, but how PKR regulates tumor necrosis factor (TNF)-induced signaling pathways is poorly understood. In the present study, we used. broblasts derived from PKR gene-deleted mice to investigate the role of PKR in TNF-induced activation of nuclear factor-kappa B (NF-kappa B), mitogen-activated protein kinases (MAPKs) and growth modulation. We found that in wild-type mouse embryonic fibroblast (MEF), TNF induced NF-kappa B activation as measured by DNA binding but deletion of PKR abolished this activation. This inhibition was associated with suppression of inhibitory subunit of NF-kappa B (I kappa B)alpha kinase (IKK) activation, I kappa B alpha phosphorylation and degradation, p65 phosphorylation and nuclear translocation, and NF-kappa B-dependent reporter gene transcription. TNF-induced Akt activation needed for IKK activation was also abolished by deletion of PKR. NF-kappa B activation was diminished in PKR-deleted cells transfected with TNF receptor ( TNFR) 1, TNFR-associated death domain and TRAF2 plasmids; NF-kappa B activated by NF-kappa B-inducing kinase, IKK or p65, however, was minimally affected. Among the MAPKs, it was interesting that whereas TNF-induced c-Jun N-terminal kinase (JNK) activation was abolished, activation of p44/p42 MAPK and p38 MAPK was potentiated in PKR-deleted cells. TNF induced the expression of NF-kappa B-regulated gene products cyclin D1, c-Myc, matrix metalloproteinase-9, survivin, X-linked inhibitor-of-apoptosis protein (IAP), IAP1, Bcl-x(L), A1/Bfl-1 and Fas-associated death domain protein-like IL-1 beta-converting enzyme-inhibitory protein in wild-type MEF but not in PKR-/- cells. Similarly, TNF induced the proliferation of wild-type cells, but this proliferation was completely suppressed in PKR-deleted cells. Overall, our results indicate that PKR differentially regulates TNF signaling; IKK, Akt and JNK were positively regulated, whereas p44/p42 MAPK and p38 MAPK were negatively regulated.
引用
收藏
页码:1201 / 1212
页数:12
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