Open AccessActivation of TNF ‐α/ NF ‐κB axis enhances CRL 4 B DCAF 11 E3 ligase activity and regulates cell cycle progression in human osteosarcoma cells
Author(s) -
Zhang Caiguo,
Chen Bin,
Jiang Kaibiao,
Lao Lifeng,
Shen Hongxing,
Chen Zhi
Publication year - 2018
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12176
Subject(s) - relb , traf2 , ubiquitin ligase , cyclin d1 , cell cycle , iκbα , microbiology and biotechnology , chemistry , cullin , tumor necrosis factor alpha , nf κb , cancer research , nfkb1 , biology , signal transduction , transcription factor , cell , ubiquitin , immunology , biochemistry , gene , tumor necrosis factor receptor
Cullin 4B, a member of the Cullins, which serve as scaffolds to facilitate the assembly of E3 ligase complexes, is aberrantly expressed in many cancers, including osteosarcoma. Recently, we observed that CUL 4B forms the CRL 4 B DCAF 11 E3 ligase, which specifically ubiquitinates and degrades the cyclin‐dependent kinase ( CDK ) inhibitor p21 Cip1 in human osteosarcoma cells. However, the underlying mechanisms regarding the aberrant expression of CUL 4B and the upstream members of this signaling pathway are mostly unknown. In this study, we demonstrate that nuclear factor kappaB ( NF ‐κB) is a direct modulator of CUL 4B expression. The CUL 4B promoter is responsive to several NF ‐κB subunits, including RelA, RelB, and c‐Rel, but not to p50 or p52. Additional studies reveal that the tumor necrosis factor alpha ( TNF ‐α)/ NF ‐κB axis pathway is activated in human osteosarcoma cells. This activation causes both CUL 4B and NF ‐κB subunits to become abundant in the nucleus of human osteosarcoma cells. The down‐regulation of individual genes, including TNFR 1 , RelA , RelB , c‐Rel , and CUL 4B , or pairs of them, including TNFR 1 + RelA , TNFR 1 + RelB , TNFR 1 + c‐Rel , and RelA + CUL 4B , has similar effects on cell growth inhibition, colony formation, cell invasion, and in vivo tumor formation, whereas the overexpression of CUL 4B in these knockdown cells significantly reverses their phenotypes. The inhibition of the TNF ‐α/ NF ‐κB pathway greatly attenuates CRL 4 B DCAF 11 E3 ligase activity and causes the accumulation of p21 Cip1 , thereby leading to cell cycle arrest at the S phase. Taken together, our results support a model in which the activation of the TNF ‐α/ NF ‐κB axis contributes to an increase in CRL 4 B DCAF 11 activity and a decrease in p21 Cip1 protein levels, thereby controlling cell cycle progression in human osteosarcoma cells.