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IKK/NF-κB signaling pathway inhibits cell-cycle progression by a novel Rb-independent suppression system for E2F transcription factors
- Source :
- Oncogene. 27:5696-5705
- Publication Year :
- 2008
- Publisher :
- Springer Science and Business Media LLC, 2008.
-
Abstract
- E2Fs are key regulators of cell-cycle progression, and their transcriptional activities are regulated by histone acetyltransferases (HATs). Retinoblastoma (Rb) family proteins (pRb, p107 and p130) bind to E2Fs and inhibit their transcriptional activities by disrupting HAT binding and recruitment of histone deacetylases. In this study, we show that IkappaB kinases (IKKalpha or IKKbeta) activation inhibits cell growth and E2F-dependent transcription in normal human fibroblasts. The inhibition of E2F by IKKs was not observed in cells lacking nuclear factor (NF)-kappaB/p65; however, it was observed in cells lacking three Rb family genes. p65 disrupted the physical interaction between activator E2Fs (F2F1, E2F2 and E2F3) and the HAT cofactor transactivation/transformation-domain associated protein, resulting in a reduction in E2F-responsive gene expression. Furthermore, IKKalpha and IKKbeta directly phosphorylated E2F4, resulting in nuclear accumulation and enhanced DNA binding of the E2F4/p130 repressor complex. Our study describes a novel growth inhibitory system that functions by Rb-independent suppression of E2Fs by the IKK/NF-kappaB signaling pathway.
- Subjects :
- Cancer Research
Repressor
Biology
Retinoblastoma Protein
Mice
Transactivation
Genetics
Animals
Humans
Phosphorylation
Promoter Regions, Genetic
E2F
Molecular Biology
E2F4
Adaptor Proteins, Signal Transducing
Histone Acetyltransferases
E2F2
Cell Nucleus
Tumor Necrosis Factor-alpha
Activator (genetics)
Cell Cycle
NF-kappa B
Transcription Factor RelA
Nuclear Proteins
DNA
E2F Transcription Factors
I-kappa B Kinase
NIH 3T3 Cells
Cancer research
biological phenomena, cell phenomena, and immunity
Signal transduction
Signal Transduction
Subjects
Details
- ISSN :
- 14765594 and 09509232
- Volume :
- 27
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....a6b6141c9d6e45aa0f29490fa2cfc338