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 IκB kinases (IKKα or IKKβ) 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)-κB/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, IKKα and IKKβ 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-κB signaling pathway.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Aggarwal BB . (2003). Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 3: 745–756.
Aggarwal BB, Pocsik E, Totpal K, Ali-Osman F . (1995). Suppression of antiproliferative effects of tumor necrosis factor by transfection of cells with human platelet-derived growth factor B/c-sis gene. FEBS Lett 357: 1–6.
Ait-Si-Ali S, Polesskaya A, Filleur S, Ferreira R, Duquet A, Robin P et al. (2000). CBP/p300 histone acetyl-transferase activity is important for the G1/S transition. Oncogene 19: 2430–2437.
Banno T, Gazel A, Blumenberg M . (2004). Effects of tumor necrosis factor-α (TNFα) in epidermal keratinocytes revealed using global transcriptional profiling. J Biol Chem 279: 32633–32642.
Boehm JS, Hession MT, Bulmer SE, Hahn WC . (2005). Transformation of human and murine fibroblasts without viral oncoproteins. Mol Cell Biol 25: 6464–6474.
Brantley DM, Chen CL, Muraoka RS, Bushdid PB, Bradberry JL, Kittrell F et al. (2001). Nuclear factor-κB (NF-κB) regulates proliferation and branching in mouse mammary epithelium. Mol Biol Cell 12: 1445–1455.
DeGregori J, Johnson DG . (2006). Distinct and overlapping roles for E2F family members in transcription, proliferation and apoptosis. Curr Mol Med 6: 739–748.
Delhase M, Hayakawa M, Chen Y, Karin M . (1999). Positive and negative regulation of IκB kinase activity through IKKβ subunit phosphorylation. Science 284: 309–313.
Ferreira R, Naguibneva I, Pritchard LL, Ait-Si-Ali S, Harel-Bellan A . (2001). The Rb/chromatin connection and epigenetic control: opinion. Oncogene 20: 3128–3133.
Frolov MV, Dyson NJ . (2004). Molecular mechanisms of E2F-dependent activation and pRB-mediated repression. J Cell Sci 117: 2173–2181.
Hahn WC, Dessain SK, Brooks MW, King JE, Elenbaas B, Sabatini DM et al. (2002). Enumeration of the simian virus 40 early region elements necessary for human cell transformation. Mol Cell Biol 22: 2111–2123.
Huang WC, Ju TK, Hung MC, Chen CC . (2007). Phosphorylation of CBP by IKKα promotes cell growth by switching the binding preference of CBP from p53 to NF-κB. Mol Cell 26: 75–87.
Karin M . (2006). Nuclear factor-κB in cancer development and progression. Nature 441: 431–436.
Karin M, Ben-Neriah Y . (2000). Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu Rev Immunol 18: 621–663.
Lang SE, McMahon SB, Cole MD, Hearing P . (2001). E2F transcriptional activation requires TRRAP and GCN5 cofactors. J Biol Chem 276: 32627–32634.
Li Q, Verma IM . (2002). NF-κB regulation in the immune system. Nat Rev Immunol 2: 725–734.
Li Q, Withoff S, Verma IM . (2005). Inflammation-associated cancer: NF-κB is the lynchpin. Trends Immunol 26: 318–325.
Martinez-Balbas MA, Bauer UM, Nielsen SJ, Brehm A, Kouzarides T . (2000). Regulation of E2F1 activity by acetylation. EMBO J 19: 662–671.
Marzio G, Wagener C, Gutierrez MI, Cartwright P, Helin K, Giacca M . (2000). E2F family members are differentially regulated by reversible acetylation. J Biol Chem 275: 10887–10892.
McMahon SB, Van Buskirk HA, Dugan KA, Copeland TD, Cole MD . (1998). The novel ATM-related protein TRRAP is an essential cofactor for the c-Myc and E2F oncoproteins. Cell 94: 363–374.
Pasparakis M, Courtois G, Hafner M, Schmidt-Supprian M, Nenci A, Toksoy A et al. (2002). TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2. Nature 417: 861–866.
Rowland BD, Bernards R . (2006). Re-evaluating cell-cycle regulation by E2Fs. Cell 127: 871–874.
Seitz CS, Deng H, Hinata K, Lin Q, Khavari PA . (2000). Nuclear factor κB subunits induce epithelial cell growth arrest. Cancer Res 60: 4085–4092.
Seitz CS, Lin Q, Deng H, Khavari PA . (1998). Alterations in NF-κB function in transgenic epithelial tissue demonstrate a growth inhibitory role for NF-κB. Proc Natl Acad Sci USA 95: 2307–2312.
Spyridopoulos I, Principe N, Krasinski KL, Xu S, Kearney M, Magner M et al (1998). Restoration of E2F expression rescues vascular endothelial cells from tumor necrosis factor-α-induced apoptosis. Circulation 98: 2883–2890.
Takahashi Y, Rayman JB, Dynlacht BD . (2000). Analysis of promoter binding by the E2F and pRB families in vivo: distinct E2F proteins mediate activation and repression. Genes Dev 14: 804–816.
Taubert S, Gorrini C, Frank SR, Parisi T, Fuchs M, Chan HM et al. (2004). E2F-dependent histone acetylation and recruitment of the Tip60 acetyltransferase complex to chromatin in late G1. Mol Cell Biol 24: 4546–4556.
Tergaonkar V, Correa RG, Ikawa M, Verma IM . (2005). Distinct roles of IκB proteins in regulating constitutive NF-κB activity. Nat Cell Biol 7: 921–923.
Trimarchi JM, Lees JA . (2002). Sibling rivalry in the E2F family. Nat Rev Mol Cell Biol 3: 11–20.
Trouche D, Cook A, Kouzarides T . (1996). The CBP co-activator stimulates E2F1/DP1 activity. Nucleic Acids Res 24: 4139–4145.
Tu Z, Prajapati S, Park KJ, Kelly NJ, Yamamoto Y, Gaynor RB . (2006). IKKα regulates estrogen-induced cell cycle progression by modulating E2F1 expression. J Biol Chem 281: 6699–6706.
Wang CY, Mayo MW, Baldwin AS . (1996). TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-κB. Science 274: 784–787.
Acknowledgements
We thank M Ikeda, K Ohtani, S Sugano, T Doi, MD Cole, G Leone, DV Goeddel, J Sage and T Jacks for providing the materials; K Tobiume, E Oda-Sato, Y Abe, I Uehara, W Nakajima and M Ando for the useful discussion, and Y Asano, H Hiroike and M Kawagoe for technical assistance. This work was supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
Author information
Authors and Affiliations
Corresponding author
Additional information
Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)
Supplementary information
Rights and permissions
About this article
Cite this article
Araki, K., Kawauchi, K. & Tanaka, N. IKK/NF-κB signaling pathway inhibits cell-cycle progression by a novel Rb-independent suppression system for E2F transcription factors. Oncogene 27, 5696–5705 (2008). https://doi.org/10.1038/onc.2008.184
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2008.184
Keywords
This article is cited by
-
Doxorubicin induces an alarmin-like TLR4-dependent autocrine/paracrine action of Nucleophosmin in human cardiac mesenchymal progenitor cells
BMC Biology (2021)
-
Putting the pieces together: How is the mitochondrial pathway of apoptosis regulated in cancer and chemotherapy?
Cancer & Metabolism (2014)
-
ERK-associated changes in E2F4 phosphorylation, localization and transcriptional activity during mitogenic stimulation in human intestinal epithelial crypt cells
BMC Cell Biology (2013)
-
Acute inhibition of TAK1 protects against neuronal death in cerebral ischemia
Cell Death & Differentiation (2011)
-
IKK-dependent, NF-κB-independent control of autophagic gene expression
Oncogene (2011)