Activation of TNF‐α/NF‐κB axis enhances CRL4BDCAF11 E3 ligase activity and regulates cell cycle progression in human osteosarcoma cells

Autor: Caiguo Zhang, Bin Chen, Kaibiao Jiang, Lifeng Lao, Hongxing Shen, Zhi Chen
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: Molecular Oncology, Vol 12, Iss 4, Pp 476-494 (2018)
Druh dokumentu: article
ISSN: 1878-0261
1574-7891
DOI: 10.1002/1878-0261.12176
Popis: 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 CUL4B forms the CRL4BDCAF11 E3 ligase, which specifically ubiquitinates and degrades the cyclin‐dependent kinase (CDK) inhibitor p21Cip1 in human osteosarcoma cells. However, the underlying mechanisms regarding the aberrant expression of CUL4B 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 CUL4B expression. The CUL4B 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 CUL4B and NF‐κB subunits to become abundant in the nucleus of human osteosarcoma cells. The down‐regulation of individual genes, including TNFR1, RelA, RelB, c‐Rel, and CUL4B, or pairs of them, including TNFR1 + RelA, TNFR1 + RelB, TNFR1 + c‐Rel, and RelA+CUL4B, has similar effects on cell growth inhibition, colony formation, cell invasion, and in vivo tumor formation, whereas the overexpression of CUL4B in these knockdown cells significantly reverses their phenotypes. The inhibition of the TNF‐α/NF‐κB pathway greatly attenuates CRL4BDCAF11 E3 ligase activity and causes the accumulation of p21Cip1, 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 CRL4BDCAF11 activity and a decrease in p21Cip1 protein levels, thereby controlling cell cycle progression in human osteosarcoma cells.
Databáze: Directory of Open Access Journals
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