411 research outputs found
SMYD3-mediated lysine methylation in the PH domain is critical for activation of AKT1
No full textAKT1 is a cytosolic serine/threonine kinase that is overexpressed in various types of cancer and has a central role in human tumorigenesis. Although it is known that AKT1 is post-translationally modified in various ways including phosphorylation and ubiquitination, methylation has not been reported so far. Here we demonstrate that the protein lysine methyltrasnferase SMYD3 methylates lysine 14 in the PH domain of AKT1 both in vitro and in vivo. Lysine 14-substituted AKT1 shows significantly lower levels of phosphorylation at threonine 308 than wild-type AKT1, and knockdown of SMYD3 as well as treatment with a SMYD3 inhibitor significantly attenuates this phosphorylation in cancer cells. Furthermore, substitution of lysine 14 diminishes the plasma membrane accumulation of AKT1, and cancer cells overexpressing lysine 14-substiuted AKT1 shows lower growth rate than those overexpressing wild-type AKT1. These results imply that SMYD3-mediated methylation of AKT1 at lysine 14 is essential for AKT1 activation and that SMYD3-mediated AKT1 methylation appears to be a good target for development of anti-cancer therapy
Skeleton on a Path: A Lyric Biography of Matsuo Basho
No full textThis thesis has been embargoed for 10 years and will not be available until April 2028 at the earliest.This thesis is a lyric biography of the life and reputation of the 17th century Japanese poet, Matsuo Basho. In addition to providing a retelling of his biography, the thesis also offers creative speculations and analysis of various aspects of the poet’s work. In additional, the thesis follows the author in his travel to Japan, where he recounts his experiences with various locations that have become the topics of Basho’s travel diaries and poems. Finally, the thesis analyzes key figures in the East and the West after Basho’s era, in an attempt to understand more about the legacy of the poet through analysis of those he influenced.2028-04-2
Abstract 4041: SUV39H2 inhibition enhances sensitivity of breast cancer cells to doxorubicin through downregulation of γ-H2AX production
No full textAbstract
Accumulating evidence has demonstrated the biological importance of protein methyltransferases in human tumorigenesis, and several small molecular inhibitors targeting these enzymes have been developed. Moreover, inhibiting pathways involved in DNA repair has been shown to enhance the cytotoxicity of DNA-damaging agents. Herein, we report the development of a potent SUV39H2 inhibitor (OTS193320) that decreases global histone H3 lysine 9 tri-methylation (H3K9me3) levels in cancer cells and attenuates cancer cell proliferation, and suppresses the tumor growth in mouse xenograft models. SUV39H2 (Suppressor of variegation 3-9 homolog 2), is a protein methyltransferase known to methylate histone H3 at lysine 9 (H3K9), and recently reported to methylate histone H2AX at lysine 134, which enhances the accumulation of phosphorylated H2AX (γ-H2AX) and regulates the DNA repair pathway in human cancer. SUV39H2 is highly expressed in many cancer types, including lung and breast cancers, while its expression levels are restricted to testis in normal adult tissues. Exposure of OTS193320 to two triple negative breast cancer cell lines attenuated H3K9me3 levels in a dose-dependent manner and triggered apoptotic cell death. Combination of OTS193320 and doxorubicin (DOX) resulted in reduction of γ-H2AX levels compared to single agent DOX, as visualized on western blot and immunocytochemical analysis. Furthermore, combination therapy attenuated the levels of p53-binding protein 1, which is reported to co-localize with γ-H2AX foci, compared to single agent DOX. Cell viability assays demonstrated a significant growth suppressive effect when OTS193320 was combined with DOX, compared to single agent treatment of either drug, suggesting chemosensitization to DOX. Importantly, in a mouse xenograft model of A549 lung cancer cells, we observed a tumor growth inhibition of 60.8% at day 14 with 25mg/kg intravenous administration of the inhibitor, without significant body weight loss or toxicity. Immunohistochemical staining of tumors treated with the inhibitor demonstrated a significantly lower number of Ki-67 positive cells and attenuated distribution patterns of H3K9me3 compared to the control tumors. Collectively, our results demonstrate that SUV39H2 inhibition may be a promising approach to develop a novel class of anti-cancer treatment.
Citation Format: Theodore Vougiouklakis, Vassiliki Saloura, Yo Matsuo, Yusuke Nakamura. SUV39H2 inhibition enhances sensitivity of breast cancer cells to doxorubicin through downregulation of γ-H2AX production [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4041. doi:10.1158/1538-7445.AM2017-4041</jats:p
Richard Flanagan’s The Narrow Road to the Deep North and Matsuo Basho’s Oku no Hosomichi
No full textThis paper investigates Australian author Richard Flanagan’s novel, The Narrow Road to the Deep North, and attempts to clarify the reason why Flanagan chose this title, which is linked to the travel writings of the Japanese author Matsuo Basho, for his novel. The novel focuses on the central character’s prisoner of war experience on the Thai-Burma Death Railway during World War II, and depicts the POW camp as well as cruel Japanese behaviour and atrocities in a realistic way. The work seems to provide a postcolonial framework in the sense that there is a colonial and postcolonial relationship between the colonizer, and the colonized. However, in this novel, the colonizer is Eastern, and the colonized is Western, and this fact reverses postcolonial theory which postulates a structure in which the colonizer is usually considered as Western and the colonized, Eastern. Postcolonial theory, thus, cannot be applied in this novel, which attempts to fuse the two opposites, the Western view and the Eastern view, through the work of the Japanese poet. As a result, Flanagan, in writing The Narrow Road to the Deep North, goes beyond being a postcolonial writer to become a writer in a globalizing age
Intercalation of polypyrrole into graphite oxide
No full textIn this paper we report on the insertion of polypyrrole into layered graphite oxide. This was achieved by using the exfoliating and re-stacking properties of the host. The resulting intercalated product was characterized by powder X-ray diffraction, FT-IR spectroscopy, thermogravimetric analysis and scanning electron microscopy. (c) 2006 Elsevier B.V. All rights reserved.PT: J; CR: *ACS, 1996, ACS SYM SER, P622 BISSESSUR R, 2001, CHEM COMMUN 0907, P1598 BISSESSUR R, 2003, J MATER CHEM, V13, P44 BISSESSUR R, 2004, J MATER SCI, V39, P119 CASSAGNEAU T, 1998, ADV MATER, V10, P877 CASSAGNEAU T, 2000, LANGMUIR, V16, P7318 DING RF, 2003, POLYM DEGRAD STABIL, V81, P473 HUMMERS WS, 1958, J AM CHEM SOC, V80, P1339 KANATZIDIS MG, 1993, CHEM MATER, V5, P595 KOVTYUKHOVA NI, 1999, CHEM MATER, V11, P771 LIU ZH, 2002, LANGMUIR, V18, P4926 MATSUO Y, 1997, CARBON, V35, P113 MATSUO Y, 1998, CHEM MATER, V10, P2266 MATSUO Y, 2002, J MATER CHEM, V12, P1592 NAKAJIMA T, 1988, CARBON, V26, P357 WANG L, 1995, CHEM MATER, V7, P1753 WU CG, 1989, POLYM MATER SCI ENG, V61, P969 XIAO M, 2002, POLYMER, V43, P2245 XIAO P, 2000, CARBON, V38, P623; NR: 19; TC: 0; J9: SYNTHET METAL; PG: 5; GA: 093UXSource type: Electronic(1
Abstract 342: WHSC1L1-mediated EGFR mono-methylation enhances the cytoplasmic and nuclear oncogenic activity of EGFR in head and neck cancer
No full textAbstract
While multiple post-translational modifications have been reported to regulate the function of epidermal growth factor receptor (EGFR), the effect of protein methylation on its function has not been well characterized. In this study, we show that WHSC1L1 mono-methylates lysine 721 in the tyrosine kinase domain of EGFR, and that this methylation leads to enhanced activation of its downstream ERK cascade without EGF stimulation. We also show that EGFR K721 mono-methylation not only affects the function of cytoplasmic EGFR, but also that of nuclear EGFR. WHSC1L1-mediated methylation of EGFR in the nucleus enhanced its interaction with PCNA in squamous cell carcinoma of the head and neck (SCCHN) cells and resulted in enhanced DNA synthesis and cell cycle progression. Overall, our study demonstrates the multifaceted oncogenic function of the protein lysine methyltransferase WHSC1L1 in SCCHN, which is mediated through direct non-histone methylation of the EGFR protein with effects both in its cytoplasmic and nuclear functions.
Citation Format: Vassiliki Saloura, Theodore Vougiouklakis, Makda Zewde, Xiaolan Deng, Kazuma Kiyotani, Jae-Hyun Park, Yo Matsuo, Mark Lingen, Naoshi Dohmae, Takehiro Suzuki, Ryuji Hamamoto, Yusuke Nakamura. WHSC1L1-mediated EGFR mono-methylation enhances the cytoplasmic and nuclear oncogenic activity of EGFR in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 342. doi:10.1158/1538-7445.AM2017-342</jats:p
The Study on Isei of “Ittosai Sensei Kenpousyo" : Focusing on the relation of Itai・Dotai and Tai・Yo
No full textThe purpose of this study is to consider Isei of “Ittosai sensei kenpousyo" based on Itai・Doutai and Tai・Yo which are relations of Kegon-thought. Ittouryu is one of Ryuha that had a great effect on modern Kendo formation and “Ittosai sensei kenpousyo" is one of Ittouryu works.
We tried to examine the meaning and content of the term of Isei based on Kegonthought. Because this work is greatly influenced by Jiriron of Kegon-thought. Therefore we supposed Isei influenced by Kegon-thought. Here are the results.
Isei is spouting dynamics from resolute mind. And I and Sei are essentially different in its being but they are also a unit in its function. Here I is Doutai and Sei is Itai and Isei is two as well as one and one as well as two. Therefore there in no time the context. But when we think of Isei in logical reasoning, I is ahead because no I no Sei. Also Isei is based on Jiri. According to this aspect, we must train mind and spirit as well as technique to acquire Isei in Kendo
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