Post-translational modifications regulating the activity and function of heme oxygenase

• Project/Area Number: 16K07307
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: Kurume University
• Principal Investigator: Higashimoto Yuichiro 久留米大学, 医学部, 教授 (40352124)
• Co-Investigator(Kenkyū-buntansha): 坂口 達也 久留米大学, 医学部, 助教 (00757031) ; 松井 孝憲 久留米大学, 医学部, 講師 (10425233)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: ヘムオキシゲナーゼ / 翻訳後修飾

Outline of Final Research Achievements

We investigated the subcellular localization and the potential regulation of heme oxygenase-1 (HO-1) by post-translational modifications. 1) An in silico analysis of the human HO-1 protein predicts a number of potential sites for post-translational modifications. 2) LPS and cadmium treatment of isolated murine peritoneal macrophages resulted in HO-1 translocation to caveolae. 3) Heme and hypoxia treatment of NIH313 and HCT116 resulted in HO-1 translocation to nuclei. 4) Co-PPX treatment of rat renal cell resulted in HO-1 translocation to mitochondria. 5) Nuclear HO-1 revealed two acetylation sites located at Lys243 and Lys256. 6) The acetylation is crucial for nuclear HO-1-enhanced tumor progression in vitro.

Academic Significance and Societal Importance of the Research Achievements

ヘムオキシゲナーゼ(HO)は、生体内で代謝的にCOを生成する唯一の酵素であり、内因性のCOの大部分は、HO反応によって生成される。HOはこれまで小胞体膜結合型酵素として知られていたが、本研究では、各種疾患由来細胞においては、その局在性、活性発現が変化することが明らかになった。これによりHO-1の局在変化と活性異常が疾患発症と関連があることが示唆され、HO-1の発現と活性を制御することが疾患治療につながる可能性を見出した。

Research Products

• [Journal Article] Selection of DNA aptamer that blocks the fibrillogenesis of a proteolytic amyloidogenic fragment of β2 m. (2018)
  • Author(s): Fukasawa K, Higashimoto Y, Ando Y, Motomiya Y
  • Journal Title: Ther Apher Dial Volume: 22 Issue: 1 Pages: 61-66
  • DOI: 10.1111/1744-9987.12591
  • Peer Reviewed / Open Access
• [Journal Article] Advanced glycation end products evoke inflammatory reactions in proximal tubular cells via autocrine production of dipeptidyl peptidase-4 (2018)
  • Author(s): Kaifu Kumiko、Ueda Seiji、Nakamura Nobutaka、Matsui Takanori、Yamada-Obara Nana、Ando Ryotaro、Kaida Yusuke、Nakata Masami、Matsukuma-Toyonaga Maki、Higashimoto Yuichiro、Fukami Kei、Suzuki Yusuke、Okuda Seiya、Yamagishi Sho-ichi
  • Journal Title: Microvascular Research Volume: 120 Pages: 90-93
  • DOI: 10.1016/j.mvr.2018.07.004
  • Peer Reviewed / Open Access
• [Journal Article] Crucial role of rage in inappropriate increase of smooth muscle cells from patients with pulmonary arterial hypertension. (2018)
  • Author(s): Nakamura K, Sakaguchi M, Matsubara H, Akagi S, Sarashina T, Ejiri K, Akazawa K, Kondo M, Nakagawa K, Yoshida M, Miyoshi T, Ogo T, Oto T, Toyooka S, Higashimoto Y, Fukami K, Ito H.
  • Journal Title: PLoS One Volume: 13 Issue: 9 Pages: 1-11
  • DOI: 10.1371/journal.pone.0203046
  • Peer Reviewed / Open Access
• [Journal Article] RAGE-aptamer Blocks the Development and Progression of Experimental Diabetic Nephropathy. (2017)
  • Author(s): Matsui, T., Higashimoto, Y., Nishino, Y., Nakamura, N., Fukami, K., Yamagishi, S.
  • Journal Title: Diabetes Volume: 66 Issue: 1 Pages: 1683-1695
  • DOI: 10.1038/s41598-018-21176-5
  • NAID: 40021434304
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Methylglyoxal-derived hydroimidazolone-1 evokes inflammatory reactions in endothelial cells via an interaction with RAGE. (2017)
  • Author(s): Ishibashi, Y., Matsui, T., Nakamura, N., Sotokawauchi, A., Higashimoto, Y., Yamagishi, S.
  • Journal Title: Diabetes Vasc. Dis. Res. Volume: 14 Issue: 5 Pages: 450-453
  • DOI: 10.1177/1479164117715855
  • Peer Reviewed
• [Journal Article] RAGE-aptamer inhibits the growth and liver metastasis of melanoma in nude mice. (2017)
  • Author(s): Nakamura, N., Matsui, T., Ishibashi, Y., Sotokawauchi, A., Fukami, K., Higashimoto, Y., Yamagishi, S.
  • Journal Title: Mol. Med. Volume: 23 Issue: 1 Pages: 295-306
  • DOI: 10.2119/molmed.2017.00099
  • Peer Reviewed / Open Access
• [Journal Article] N-butanol extracts of noni suppress advanced glycation end products (AGEs)-induced inflammatory and thrombotic reactions in endothelial cells through its anti-oxidative properties (2017)
  • Author(s): Ishibashi, Y., Matsui, T., Abe, Y., Sakaguchi, T., Higashimoto, Y., Yamagishi, S.
  • Journal Title: BMC Complementary and Alternative Medicine Volume: 17(1) Issue: 1 Pages: 137-137
  • DOI: 10.1186/s12906-017-1641-3
  • Peer Reviewed / Open Access
• [Journal Article] Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor. (2017)
  • Author(s): 1.J. Taira, Y. Kida, K. Inatomi, H. Komatsu, Y. Higashimoto, H. Sakamoto.
  • Journal Title: J. Biochemistry Volume: 印刷中 Pages: 113-122
  • DOI: 10.1093/jb/mvx007
  • NAID: 40021299788
  • Peer Reviewed / Open Access
• [Journal Article] Phytochemicals against advanced glycation end products (AGEs) and the receptor system (2017)
  • Author(s): Yamagishi, S., Matsui, T., Ishibashi, Y., Abe, Y., Sakaguchi, T., Higashimoto, Y.
  • Journal Title: Current Pharmaceutical Design Volume: 23(8) Issue: 8 Pages: 1135-1141
  • DOI: 10.2174/1381612822666161021155502
  • Peer Reviewed
• [Journal Article] Glycation and cardiovascular disease in diabetes: A perspective on the concept of metabolic memory. (2017)
  • Author(s): Yamagishi SI, Nakamura N, Matsui T.
  • Journal Title: J Diabetes. Volume: 9 Issue: 2 Pages: 141-148
  • DOI: 10.1111/1753-0407.12475
  • Peer Reviewed
• [Journal Article] Influence of heparin molecular size on the induction of C- terminal unfolding in β2-microglobulin. (2016)
  • Author(s): Fukasawa K, Higashimoto Y, Motomiya Y, Uji Y, Ando Y.
  • Journal Title: Mol Biol Res Commun. Volume: 5 Pages: 225-232
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Protective Role of PEDF-Derived Synthetic Peptide against Experimental Diabetic Nephropathy. (2016)
  • Author(s): Ishibashi, Y., Matsui, T., Taira, J., Higashimoto, Y., Yamagishi, S.
  • Journal Title: Hormone and Metabolic Research Volume: 48(09) Issue: 09 Pages: 613-619
  • DOI: 10.1055/s-0042-108448
  • Peer Reviewed
• [Journal Article] β2-ミクログロブリンの折り込み障害 (2016)
  • Author(s): 本宮善恢、東元祐一郎、宇治義則
  • Journal Title: 腎と骨代謝 Volume: 29 Pages: 207-215
  • Peer Reviewed
• [Journal Article] Sulforaphane reduces advanced glycation end products (AGEs)-induced inflammation in endothelial cells and rat aorta. (2016)
  • Author(s): Matsui T, Nakamura N, Ojima A, Nishino Y, Yamagishi SI.
  • Journal Title: Nutr Metab Cardiovasc Dis. Volume: 26 Issue: 9 Pages: 797-807
  • DOI: 10.1016/j.numecd.2016.04.008
  • Peer Reviewed
• [Journal Article] Serum Levels of Growth Differentiation Factor 11 Are Independently Associated with Low Hemoglobin Values in Hemodialysis Patients. (2016)
  • Author(s): Yamagishi S, Matsui T, Kurokawa Y, Fukami K.
  • Journal Title: Biores Open Access. Volume: 5 Issue: 1 Pages: 155-158
  • DOI: 10.1089/biores.2016.0015
  • Peer Reviewed
• [Journal Article] Protective role of sulphoraphane against vascular complications in diabetes. (2016)
  • Author(s): Yamagishi S, Matsui T.
  • Journal Title: Pharm Biol. Volume: 54 Issue: 10 Pages: 2329-2339
  • DOI: 10.3109/13880209.2016.1138314
  • Peer Reviewed
• [Presentation] マイクロアレイのメタ解析による遺伝子の持つ機能範囲の推定 (2018)
  • Author(s): 坂口達也、東元祐一郎
  • Organizer: 平成30年度日本生化学会九州支部例会
• [Presentation] ヘムオキシゲナーゼ-2に対するカベオリン-1由来ペプチドのへミン競合的な結合と酵素活性阻害 (2018)
  • Author(s): 平順一、武本美沙希、上岡歩美、東元祐一郎、坂本寛
  • Organizer: 平成30年度日本生化学会九州支部例会
• [Presentation] Selection of DNA Aptamer that Block the Fibrillogenesis of a Proteolytic Amyloidogenic Fragment of β2m (ΔN6β2m) (2018)
  • Author(s): 東元祐一郎、深澤伽音、安東 由喜雄、本宮 善恢
  • Organizer: 第4回日本核酸医薬学会年会
• [Presentation] 終末糖化産物受容体(RAGE)アプタマーは動物モデルの糖尿病性腎症の発症・憎悪、悪性黒色腫の増殖・転移を抑制する (2018)
  • Author(s): 松井孝憲、東元祐一郎、中村信孝、山岸昌一
  • Organizer: 第4回日本核酸医薬学会年会
• [Presentation] 発現相関遺伝子群による遺伝子の影響範囲推定法の開発 (2018)
  • Author(s): 坂口達也、東元祐一郎
  • Organizer: 第7回生命医薬情報学連合大会
• [Presentation] 発現相関遺伝子群による包括的な遺伝子機能推定法の開発 (2018)
  • Author(s): 坂口達也、東元祐一郎
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] 終末糖化産物受容体(RAGE)アプタマーは動物の糖尿病腎症の発症・増悪と悪性黒色腫の増殖・転移を阻害する (2018)
  • Author(s): 松井孝憲、中村信孝、東元祐一郎、山岸昌一
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] 変異型β2ミクログロブリン特異的アプタマーによる透析アミロイド―シスの抑制効果 (2017)
  • Author(s): 東元祐一郎
  • Organizer: 第3回アプタマー勉強会
  • Invited
• [Presentation] 核酸アプタマーの医薬診断薬としての可能性 (2017)
  • Author(s): 東元祐一郎
  • Organizer: 第71回久留米医学会総会
  • Invited
• [Presentation] 血清中のエリスロフェロンの測定と夾雑物質の有無 (2017)
  • Author(s): 東元祐一郎
  • Organizer: 医療法人翠悠会研究セミナー
  • Invited
• [Presentation] 変異型β２ミクログロブリン(ΔN6β2m)特異的DNAアプタマーによるアミロイド凝集抑制効果の検討 (2017)
  • Author(s): 深澤伽音、東元祐一郎、安東由喜雄、本宮善恢
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Presentation] マイクロアレイのメタ解析による色素上皮由来因子PEDFの関連遺伝子探索 (2017)
  • Author(s): 坂口達也、東元祐一郎
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Presentation] AGEアプタマーはバルーンにより損傷したラット頚動脈中における新生血管内膜の過形成を抑制する (2016)
  • Author(s): 東元祐一郎、尾嶋亜弥子、小田えり子、松井孝憲、山岸昌一
  • Organizer: 第2回日本核酸医薬学会年会
  • Place of Presentation: 東京理科大学（東京都葛飾区）
  • Year and Date: 2016-11-16
• [Presentation] 終末糖化産物受容体（RAGE）のDNAアプタマーはラットの糖尿病腎症を改善する (2016)
  • Author(s): 松井孝憲、東元祐一郎、山岸昌一
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-09-26
• [Presentation] RAGE-DNA aptamerはAGEs-RAGE系を抑制しMR活性腎障害を改善する (2016)
  • Author(s): 田口顕正、山岸昌一、松井孝憲、東元祐一郎、淺沼克彦、上田誠二、深水圭
  • Organizer: 第59回日本腎臓学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-06-17
• [Presentation] エリスロフェロン測定系での血清中夾雑タンパクの影響 (2016)
  • Author(s): 田中賢治、東元祐一郎、深澤伽音、本宮康樹、益田眞理、大貫雅弘、本宮善恢
  • Organizer: 第61回日本透析医学会学術集会・総会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2016-06-10
• [Presentation] RAGE－DNA APTAMER IMPROVES MR－ASSOCIATED RENAL INJURY THROUGH RAC1－MEDIATED MR ACTIVATION (2016)
  • Author(s): 田口顕正、山岸昌一、松井孝憲、東元祐一郎、淺沼克彦、上田誠二、深水圭
  • Organizer: 第53回欧州腎臓学会・欧州透析移植学会
  • Place of Presentation: Austria Center Vienna (オーストリア・ウィーン）
  • Year and Date: 2016-05-22
  • Int'l Joint Research