Proceedings of the Japan Academy, Series B
Online ISSN : 1349-2896
Print ISSN : 0386-2208
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  • Yosuke YAMADA, Yasuhiro YAMADA
    Volume 94 (2018) Issue 6 Pages 235-247
    Released: June 11, 2018
    JOURNALS FREE ACCESS FULL-TEXT HTML

    There is increasing evidence that cancer cells acquire epigenetic abnormalities as well as genetic mutations during cancer initiation, maintenance, and progression. However, the role of epigenetic regulation in cancer development, especially at the organismal level, remains to be elucidated. Here, we describe the causative role of epigenetic abnormalities in cancer, referring to our in vivo studies using induced pluripotent stem cell technology. We first summarize epigenetic reorganization during cellular reprogramming and introduce our in vivo reprogramming system for investigating the impact of dedifferentiation-driven epigenetic disruption in cancer development. Accordingly, we propose that particular types of cancer, in which causative mutations are not often detectable, such as pediatric cancers like Wilms’ tumor, may develop mainly through alterations in epigenetic regulation triggered by dedifferentiation. Finally, we discuss issues that still remain to be resolved, and propose possible future applications of in vivo reprogramming to study cancer and other biological phenomena including organismal aging.

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  • Takashi MINO, Osamu TAKEUCHI
    Volume 94 (2018) Issue 6 Pages 248-258
    Released: June 11, 2018
    JOURNALS FREE ACCESS FULL-TEXT HTML

    Cytokines are critical mediators of inflammation and host immune defense. Cytokine production is regulated at both transcriptional and post-transcriptional levels. Post-transcriptional damping of inflammatory mRNAs is mediated by a set of RNA binding proteins (RBPs) interacting with cis-elements, such as AU-rich elements (ARE) and stem-loop structures. Whereas ARE-binding proteins such as tristetraprolin and a stem-loop recognizing protein, Roquin, downregulate cytokine mRNA abundance by recruiting a CCR4-NOT deadenylase complex, another stem-loop RBP, Regnase-1, acts as an endoribonuclease, directly degrading target cytokine mRNAs. These RBPs control translation-active or -inactive mRNAs in distinct intracellular locations. The presence of various RBPs regulating mRNAs in distinct locations enables elaborate control of cytokines under inflammatory conditions. Dysregulation of cytokine mRNA decay leads to pathologies such as the development of autoimmune diseases or impaired activation of immune responses. Here we review current knowledge about the post-transcriptional regulation of immune responses by RBPs and the importance of their alteration during inflammatory pathology and autoimmunity.

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