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発表内容

Title:
How does oxidative stress control cell death and cell proliferation?

Hiroyasu Nakano
Associate Professor
Department of Immunology
Juntendo University Graduate School of Medicine

Abstract:
Reactive oxygen species (ROS) control a variety of cellular responses including prevention of bacterial infection, cell death, cellular senescence, and carcinogenesis. We previously reported that the transcription factor of nuclear factor of k B (NF- k B) suppresses tumor necrosis factor (TNF) a -induced ROS production that subsequently induces sustained MAP kinase activation and programmed necrosis, which is now referred to as necroptosis ( Sakon et al, EMBO J 2003 ). Moreover, we also showed that cellular FLICE inhibitory protein (c-FLIP) plays a crucial role in NF- k B-dependent survival signals through preventing caspase activation and ROS accumulation ( Nakajima et al EMBO J 2006; Oncogene 2008 ). However, the mechanisms underlying ROS-dependent cell death are not fully understood.
Apoptosis is a process of programmed cell death that is induced by various stimuli and is observed during developmental processes. Moreover, apoptosis as well as necroptosis is tightly associated with oxidative stress. Several lines of evidence have suggested that dying cells are critically involved in various cellular responses, including inflammation, immune regulation, tissue repair, and carcinogenesis. Notably, apoptotic cells promote wound healing and tissue regeneration through the production of prostaglandin E 2 (PGE 2 ) in a caspase-dependent manner. InDrosophila , apoptotic cells release Wingless (Wg) and Decapentaplegic (Dpp ) , Drosophilahomologues of Wnt and TGF- b , respectively, which subsequently induce the proliferation of surrounding cells to maintain tissue homeostasis. These phenomena are referred to as “compensatory proliferation.” Although these studies have suggested that dying cells might play a crucial role in maintaining tissue homeostasis, the mechanisms that underlie tissue homeostasis that is regulated by dying cells are not fully understood. A study of a wound model in zebrafish showed that ROS produced by dying cells plays a crucial role in the recruitment of neutrophils to a wound site; however, it is currently unknown whether oxidative stress is involved in compensatory proliferation.
In this seminar, I will first introduce differential contribution of ROS to necroptosis and apoptosis using various NF- k B activation-deficient cells. Later, I will present our very recent work that highlights a previously unappreciated role for interleukin 11 in linking oxidative stress and compensatory proliferation.

References:
1. Nishina, T., S. Komazawa-Sakon, S. Yanaka, X. Piao, D.M. Zheng, J.H. Piao, Y. Kojima, S. Yamashina, E. Sano, T. Putoczki, T. Doi, T. Ueno, J. Ezaki, H. Ushio, M. Ernst, K. Tsumoto, K. Okumura, and H. Nakano. 2012. Interleukin-11 links oxidative stress and compensatory proliferation. Sci Signal 5:ra5.

2. Tokunaga, F., T. Nakagawa, M. Nakahara, Y. Saeki, M. Taniguchi, S. Sakata, K. Tanaka, H. Nakano, and K. Iwai. 2011. SHARPIN is a component of the NF-kappaB-activating linear ubiquitin chain assembly complex. Nature 471:633-636.

3. Ushio, H., T. Ueno, Y. Kojima, M. Komatsu, S. Tanaka, A. Yamamoto, Y. Ichimura, J. Ezaki, K. Nishida, S. Komazawa-Sakon, F. Niyonsaba, T. Ishii, T. Yanagawa, E. Kominami, H. Ogawa, K. Okumura, and H. Nakano. 2011. Crucial role for autophagy in degranulation of mast cells. J Allergy Clin Immunol 127:1267-1276 e1266.

4. Piao, J.H., M. Hasegawa, B. Heissig, K. Hattori, K. Takeda, Y. Iwakura, K. Okumura, N. Inohara, and H. Nakano. 2011. Tumor Necrosis Factor Receptor-associated Factor (TRAF) 2 Controls Homeostasis of the Colon to Prevent Spontaneous Development of Murine Inflammatory Bowel Disease. J Biol Chem 286:17879-17888. Selected as ” Papers of the Week