RACK1 antagonizes TNF-[alpha]-induced cell death by promoting p38 activation

p38 mitogen-activated protein kinase (MAPK) activity has been reported to either promote or suppress cell death, which depends on cell type and stimulus. Our previous report indicates that p38 exerts a protective role in tumor necrosis factor (TNF)-α-induced cell death in L929 fibroblastoma cells. H...

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Bibliographic Details
Published in:Scientific reports 2015-09, Vol.5, p.14298
Main Authors: Wang, Qingyang, Zhou, Silei, Wang, Jing-yang, Cao, Junxia, Zhang, Xueying, Wang, Jing, Han, Kun, Cheng, Qianqian, Qiu, Guihua, Zhao, Yawei, Li, Xinying, Qiao, Chunxia, Li, Yan, Hou, Chunmei, Zhang, Jiyan
Format: Article
Language:English
Subjects:
Apoptosis
Cell death
Ectopic expression
Hepatocytes
Kinases
MAP kinase
MKK3 protein
Phosphorylation
Protein kinase
Tumor necrosis factor
Tumor necrosis factor-TNF
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Summary:p38 mitogen-activated protein kinase (MAPK) activity has been reported to either promote or suppress cell death, which depends on cell type and stimulus. Our previous report indicates that p38 exerts a protective role in tumor necrosis factor (TNF)-α-induced cell death in L929 fibroblastoma cells. However, key molecules regulating p38 activation remain unclear. Here, we show that ectopic expression of scaffold protein receptor for activated C kinase 1 (RACK1) suppressed TNF-α-induced cell death in L929 cells, which was associated with enhanced p38 activation. Knockdown of endogenous RACK1 expression exhibited opposite effects. The protective role of RACK1 in TNF-α-induced cell death diminished upon blockade of p38 activation. Therefore, RACK1 antagonizes TNF-α-induced cell death through, at least partially, augmenting p38 activation. Further exploration revealed that RACK1 directly bound to MKK3/6 and enhanced the kinase activity of MKK3/6 without affecting MKK3/6 phosphorylation. Similar effects of RACK1 were also observed in primary murine hepatocytes, another cell type sensitive to TNF-α-induced cell death. Taken together, our data suggest that RACK1 is a key factor involved in p38 activation as well as TNF-α-induced cell death.
ISSN:2045-2322
DOI:10.1038/srep14298