Title:
Regulation of NF- κB activation and its relation to cancer development
Jun-ichiro Inoue
Division of Molecular and Cellular Biology
Department of Cancer Biology
Institute of Medical Science, University of Tokyo ,
Abstract:
The persistent or excess activation of NF- κB causes various inflammatory and autoimmune diseases, but the molecular mechanisms that negatively regulate NF- κB activation are not fully understood. Here we show that p47, an essential factor for Golgi membrane fusion, associates with the NEMO subunit of the I k B kinase (IKK) complex upon TNF- α or IL-1 stimulation and inhibits IKK activation. p47 binds to Lys63-linked and linear polyubiquitin chains, which are conjugated to NEMO upon such stimulation. The binding of p47 to polyubiquitinated NEMO triggers the lysosomal degradation of NEMO, thereby inhibiting IKK activation. The silencing of p47 results in enhanced TNF- α or IL-1-induced IKK activation and an increased expression of genes encoding inflammatory mediators. Taken together, our results strongly suggest that p47 is critical for negatively regulating stimulation-induced IKK activation in a manner that is mechanistically distinct from the previously characterized negative regulators, such as A20 and CYLD.
We have previously reported that NF- κB is crucial for basal-like breast cancer malignancy, which led us to hypothesize that NF- κB activation is involved in maintenance of the cancer stem cells (CSCs) of breast cancer. We would like to show that constitutive and induced NF- κB activation played a positive role in CSC maintenance and propose a new model in which the NF- κB activation in non-CSCs cell-autonomously increases expression of soluble or membrane-bound ligands, which act in trans to stimulate CSCs leading to enhanced generation and maintenance of CSCs. Novel regulatory mechanisms of NF- κB activation and NF- κB-mediated maintenance of CSCs will be discussed.
References:
1. Shibata , Y., Oyama, M., Kozuka-Hata, H., Han, X., Tanaka, Y., Gohda, J. and Inoue, J. p47 negatively regulates IKK activation by inducing the lysosomal degradation of polyubiquitinated NEMO. Nat. Commun. 3:1061 doi:10.1038/ncomms2068 , 2012.
2. Yamamoto, T., Yokota, Y., Mitsuki, Y., Mizukoshi, F., Tsuchiya, T., Terahara, K., Inagaki, Y., Yamamoto, N., Kobayashi, K., and Inoue, J. Selective transmission of R5 HIV-1 over X4 HIV-1 at the dendritic cell-T cell infectious synapse is determined by the T cell activation state. PLos Pathogens 5(1): e1000279, 2009.
3. Yamazaki, K., Gohda, J., Kanayama, A., Miyamoto, Y., Sakurai, H., Yamamoto, M., Akira, S., Hayashi, H., Su, B., and Inoue, J. Two Mechanistically and Temporally Distinct NF- κB Activation Pathways in IL-1 Signaling. Sci. Signal. 2, ra66, 2009.
4. Akiyama T., Shimo Y., Yanai H., Qin J., Ohsima, D., Maruyama Y., Asaumi Y., Kitazawa J., Takayanagi H., Penninger JM., Matsumoto M., Nitta T., Takahama Y., and Inoue J. The Tumor Necrosis Factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance . Immunity 29, 423-437, 2008.
5. Akiyama, T., Maeda, S., Yamane, S., Ogino, K., Kasai , M., Kajiura, F., Matsumoto, M., and Inoue, J. Dependence of Self-tolerance on TRAF6-directed Development of Thymic Stroma. Science 308, 248-251, 2005.
