Analysis of mechanisms by which proteostasis capacity is regulated through activation of heat shock factor

• Project/Area Number: 24390081
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Yamaguchi University
• Principal Investigator: NAKAI Akira 山口大学, 医学(系)研究科(研究院), 教授 (60252516)
• Co-Investigator(Kenkyū-buntansha): FUJIMOTO Mitsuaki 山口大学, 大学院医学系研究科, 准教授 (80359900) ; HAYASHIDA Naoki 山口大学, 大学院医学系研究科, 講師 (40420517) ; TAKII Ryosuke 山口大学, 大学院医学系研究科, 助教 (00419558)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2014: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2013: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2012: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
• Keywords: 神経変性疾患 / 熱ショック / 転写 / クロマチン / プロテオスタシス / リン酸化 / 蛋白質 / ホメオスタシス / 転写因子 / リン酸

Outline of Final Research Achievements

Capacity of cellular protein homeostasis, known as proteostasis, is related with progression of age-related neurodegenerative disease and cancer. One of prominent mechanisms of the maintenance of proteostasis capacity is the heat shock response, which is regulated mainly at the level of transcription by heat shock factors (HSFs). Among mammalian HSFs, HSF4 constitutively binds to DNA under unstressed conditions. In this research project, we demonstrate a mechanism by which HSF4 activity is regulated through phosphorylation, and suggest that proteostasis capacity is regulated by a chemical modification of HSF4 under physiological conditions.

Research Products

• [Journal Article] ATF1 modulates the heat shock response by regulating the stress-inducible HSF1-transcription complex (2015)
  • Author(s): R. Takii, M. Fujimoto, K. Tan, E. Takaki, N. Hayashida, R. Nakato, K. Shirahige, and A. Nakai
  • Journal Title: Mol. Cell. Biol. Volume: 35 Issue: 1 Pages: 11-25
  • DOI: 10.1128/mcb.00754-14
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Mitochondrial SSBP1 protects cells from proteotoxic stresses by potentiating stress-induced HSF1 transcriptional activity (2015)
  • Author(s): K. Tan, M. Fujimoto, R. Takii, E. Takaki, N. Hayashida, and A. Nakai
  • Journal Title: Nat. Commun. Volume: 6 Pages: 6580-6580
  • NAID: 120005822836
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Roles of heat shock factor 1 in neuronal response to fetal environmental risks and its relevance to brain disorders (2014)
  • Author(s): K. Hashimoto-Torii, M. Torii, M. Fujimoto, A. Nakai, R. El Fatimy, V. Mezger, M. J. Ju, S. Ishii, S. Chao, K. J. Brennand, F. H. Gage, and P. Rack
  • Journal Title: Neuron Volume: 82 Issue: 3 Pages: 560-572
  • DOI: 10.1016/j.neuron.2014.03.002
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Heat shock factor 1 is required for migration and invasion of human melanoma in vitro and in vivo (2014)
  • Author(s): Y. Nakamura, M. Fujimoto, S. Fukushima, A. Nakamura, N. Hayashida, R. Takii, E. Takaki, A. Nakai, M. Muto
  • Journal Title: Cancer Lett. Volume: 354 Issue: 2 Pages: 329-335
  • DOI: 10.1016/j.canlet.2014.08.029
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 熱ショック因子によるプロテオスタシス制御と疾患 (2014)
  • Author(s): 瀧井良祐、中井 彰
  • Journal Title: 細胞工学 Volume: 33 Pages: 706-710
  • Open Access / Acknowledgement Compliant
• [Journal Article] Genome-wide DNA methylation profiling in cultured eutopic and ectopic endometrial stromal cells (2014)
  • Author(s): Y. Yamagata, K. Nishino, E. Takaki, S. Sato, R. Maekawa, A. Nakai, and N. Sugino
  • Journal Title: PLoS One Volume: 9
  • Peer Reviewed
• [Journal Article] Genome-wide DNA methylation analysis reveals a potential mechanism for the pathogenesis and development of uterine leiomyomas (2013)
  • Author(s): R. Maekawa, S. Sato, Y. Yamagata, H. Asada, I. Tamura, L. Lee, M. Okada, H. Tamura, E. Takaki, A. Nakai, and N. Sugino
  • Journal Title: PLoS One Volume: 8
  • NAID: 120005652007
  • Peer Reviewed
• [Journal Article] Regeneration of injured skeletal muscle in heat shock transcriptional factor 1-null mice (2013)
  • Author(s): S. Nishizawa, T. Koya, Y. Ohno, A. Goto, A. Ikuita, M. Suzuki, T. Ohira, T. Egawa, A. Nakai, T. Sugiura, Y. Ohira, T. Yoshioka, M. Beppu, and K. Goto
  • Journal Title: Physiol. Rep. Volume: 1
  • Peer Reviewed
• [Journal Article] Hsp90 prevents interaction between CHIP and HERG proteins to facilitate maturation of wild-type and mutant HERG proteins (2013)
  • Author(s): C. Iwai, P. Li, Y. Kurata, Y. Hoshikawa, K. Morikawa, N. Maharani, K. Higaki, T. Sasano, T. Notsu, Y. Ishido, J. Miake, Y. Yamamoto, Y. Shirayoshi, H. Ninomiya, A. Nakai, S. Murata, A. Yoshida, K. Yamamoto, M. Hiraoka, and I. Hisatome
  • Journal Title: Cardiovasc. Res. Volume: 100 Pages: 520-528
  • Peer Reviewed
• [Journal Article] Chicken IL-6 is a heat-shock gene (2013)
  • Author(s): R. Prakasam, M. Fujimoto, R. Takii, N. Hayashida, E. Takaki, K. Tan, F. Wu, S. Inouye, and A. Nakai
  • Journal Title: FEBS Lett. Volume: 587 Pages: 3541-3547
  • Peer Reviewed
• [Journal Article] Heat shock transcription factor 1-deficiency attenuates overloading-associated hypertrophy of mouse soleus muscle (2013)
  • Author(s): T. Koya, S. Nishizawa, Y. Ohno, A. Goto, A. Ikuita, M. Suzuki, T. Ohira, T. Egawa, A. Nakai, T. Sugiura, Y. Ohira, T. Yoshioka M. Beppu, and K. Goto
  • Journal Title: PLoS One Volume: 8
  • Peer Reviewed
• [Journal Article] Heat shock factor 1 accelerates hepatocellular carcinoma development by activating nuclear factor κB/ mitogen-activated protein kinase (2013)
  • Author(s): M. Chuma, N. Sakamoto, A. Nakai, S. Hige, M. Nakanishi, M. Natsuizaka, G. Suda, T. Sho, K. Hatanaka, Y. Matsuno, H. Yokoo, T. Kamiyama, A. Taketomi, G. Fujii, K. Tashiro, Y. Hikiba, M. Fujimoto, M. Asaka, and S. Maeda
  • Journal Title: Carcinogenesis Volume: 35 Pages: 272-281
  • Peer Reviewed
• [Journal Article] Glutamine protects intestinal barrier function of colon epithelial cells from ethanol by modulating Hsp70 expression. (2013)
  • Author(s): R. Akagi, M. Ohno, K. Matsubara, M. Fuiimoto, A. Nakai, and S. Inouye
  • Journal Title: Pharmacology Volume: 91 Pages: 104-111
  • Peer Reviewed
• [Journal Article] Heat shock factor-1 influences pathological lesion distribution of polyglutamine-induced neurodegeneration. (2013)
  • Author(s): N. Kondo, M. Katsuno, H. Adachi, M. Minamiyama, H. Doi, S. Matsumoto, Y. Miyazaki, M. Iida, G. Tohnai, H. Nakatsuji, S. Ishigaki, Y. Fujioka, H. Watanabe, F. Tanaka, A. Nakai, G. Sobue
  • Journal Title: Nat. Commun. Volume: 4 Pages: 1405-1405
  • Peer Reviewed
• [Journal Article] Induction of heat shock protein 70 ameliorates ultraviolet-induced photokeratitis in mice. (2013)
  • Author(s): A. Lennikov, N. Kitaichi, S. Kase, K. Noda, Y. Horie, A. Nakai, S. Ohno, S. Ishida
  • Journal Title: Int. J. Mol. Sci. Volume: 14 Pages: 2175-2189
  • NAID: 120005228266
  • Peer Reviewed
• [Journal Article] Geranylgeranylace tone suppresses noise-induced expression of proinflammatory cytokines in the cochlea. (2012)
  • Author(s): T. Nakamoto, T. Mikuriya, K. Sugahara, Y. Hirose, T. Hashimoto, H. Shimogori, R. Takii, A. Nakai, H. Yamashita
  • Journal Title: Auris Nasus Larynx Volume: 39 Pages: 270-274
  • Peer Reviewed
• [Journal Article] Association of Stat3 with HSF1 plays a critical role in G-CSF-induced cardio-protection against ischemia/reperfusion injury. (2012)
  • Author(s): H. Ma, H. Gong, Z. Chen, Y. Liang, J. Yuan, G. Zhang, J. Wu, Y. Ye, C. Yang, A. Nakai, I. Komuro, J. Ge, Y. Zou
  • Journal Title: J. Mol. Cell. Cardiol. Volume: 52 Pages: 1282-1290
  • Peer Reviewed
• [Journal Article] Heat shock factor 1 contributes to ischemia-induced angiogenesis by regulating the mobilization and recruitment of bone marrow stem/progenitor cells. (2012)
  • Author(s): M. Kubo, T.-S. Li, H. Kurazurai, Y. Takemoto, M. Ohshima, Y. Yamamoto, A. Nishimoto, A. Mikamo, M. Fujimoto, A. Nakai, K. Hamano
  • Journal Title: PLoS One Volume: 7
  • NAID: 120006985399
  • Peer Reviewed
• [Journal Article] RPA assists HSF1 access to nucleosomal DNA by recruiting histone chaperone FACT. (2012)
  • Author(s): M. Fujimoto, E. Takaki, R. Takii, K. Tan, R. Prakasam, N. Hayashida, S. Ieraura, T. Natsume, and A. Nakai
  • Journal Title: Mol. Cell Volume: 48 Pages: 182-194
  • Peer Reviewed
• [Presentation] A mitochondrial protein accelerates the heat shock response (2015)
  • Author(s): Akira Nakai
  • Organizer: EMBO workshop: the regulation of aging and proteostasis
  • Place of Presentation: Maale Hachamisha, Israel
  • Year and Date: 2015-02-15 – 2015-02-20
  • Invited
• [Presentation] 熱ショック応答によるミトコンドリア膜電位の維持 (2014)
  • Author(s): 譚克、藤本充章、瀧井良祐、高木栄一、林田直樹、中井 彰
  • Organizer: 第37回日本分子生物学会
  • Place of Presentation: パシフィコ横浜（ 横浜市）
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] 熱ショック因子HSF2は Set1/MLL複合体と相互作用する (2014)
  • Author(s): 林田直樹、高木栄一、瀧井良祐、譚克、藤本充章、中井 彰
  • Organizer: 第37回日本分子生物学会
  • Place of Presentation: パシフィコ横浜（ 横浜市）
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] 熱ショック転写因子はin vitro、in vivoにおいてヒトメラノーマ細胞の遊走能、浸潤能の維持に必要である (2014)
  • Author(s): 中村好貴、藤本充章、福島園子、中村有希子、中井彰、武藤正彦
  • Organizer: 第９回臨床ストレス応答学会
  • Place of Presentation: マスカットキューブ（ 岡山市）
  • Year and Date: 2014-11-01 – 2014-11-02
• [Presentation] 熱ショック応答とミトコンドリア (2014)
  • Author(s): 瀧井良祐、中井彰
  • Organizer: 第87回日本生化学会大会シンポジウム「 細胞ストレス応答の病態と治療の新基軸」
  • Place of Presentation: 国立京都国際会館（ 京都市）
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] HSF1-PARP相互作用がHSP70遺伝子座のクロマチン構成を調節する (2014)
  • Author(s): 藤本充章、瀧井良祐、譚克、高木栄一、林田直樹、中井彰
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 国立京都国際会館（ 京都市）
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] ミトコンドリアタンパク質が熱ショック応答を促進する (2014)
  • Author(s): 譚克、藤本充章、瀧井良祐、高木栄一、林田直樹、中井彰
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 国立京都国際会館（ 京都市）
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] Epigenomic regulation of the HSF-transcription complexes under physiological and stressed conditions (2014)
  • Author(s): Akira Nakai
  • Organizer: HSF Workshop
  • Place of Presentation: Paris, France
  • Year and Date: 2014-04-22 – 2014-04-24
  • Invited
• [Presentation] HSF1-PARP13-PARP1複合体はHSP70誘導に必要である (2014)
  • Author(s): 藤本充章、瀧井良祐、譚克、Prakasam Ram、伍方緒、高木栄一、林田直樹、中井彰
  • Organizer: 転写研究会・転写サイクル・転写代謝システム共催「冬の若手ワークショップ2014」
  • Place of Presentation: 磯辺温泉(軽井沢)
• [Presentation] 認知症治療に向けた、病原性タウ蛋白質の凝集抑制への熱ショック因子の応用 (2013)
  • Author(s): 林田直樹
  • Organizer: 第13回国際バイオテクノロジー展／技術会議 アカデミックフォーラム「創薬ツール」
  • Place of Presentation: 東京ビッグサイト(東京)
• [Presentation] 熱ショック応答におけるエピゲノム制御 (2013)
  • Author(s): 中井 彰
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: パシフィコ横浜(横浜）
  • Invited
• [Presentation] PARP13はHSF1を介するHSP70誘導に必要である (2013)
  • Author(s): 藤本充章、瀧井良祐、譚克、Prakasam Ram、伍方緒、高木栄一、林田直樹、中井 彰
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: パシフィコ横浜(横浜)
• [Presentation] Heat shock induces expression of pyrogenic cytokines in avian cells whereas it suppresses in mammalian cells (2013)
  • Author(s): Ramachandran Prakasam, Mitsuaki Fujimoto, Ryosuke Takii, Naoki Hayashida, Eiichi Takaki, Ke Tan, Sachiye Inouye, and Akira Nakai
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: パシフィコ横浜(横浜）
• [Presentation] 熱ショック因子HSF1によるヘムオキシゲナーゼ１の発現調節の修飾 (2013)
  • Author(s): 井上幸江、藤本充章、譚克、中井彰、赤木玲子
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: パシフィコ横浜(横浜）
• [Presentation] p300/CBP は回復期におけるHSF1活性を調節する (2013)
  • Author(s): 瀧井良祐、藤本充章、高木栄一、譚克、Prakasam Ram、林田直樹、中井 彰
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: パシフィコ横浜(横浜）
• [Presentation] 熱ショック因子HSF4のターゲット遺伝子の同定 (2013)
  • Author(s): 高木栄一、藤本充章、林田直樹、瀧井良祐、Prakasam Ram、譚克、伍方緒、中井 彰
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: パシフィコ横浜(横浜)
• [Presentation] 熱ショック因子 HSF2 はクロマチンを弛緩する (2013)
  • Author(s): 林田直樹、高木栄一、瀧井良祐、譚克、Prakasam Ram、家村俊一郎、夏目徹、藤本充章、中井彰
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: パシフィコ横浜(横浜)
• [Presentation] The heat shock response is modulated by ATF1/CREB members. (2013)
  • Author(s): Akira Nakai
  • Organizer: International Symposium on Transcription and Metabolism
  • Place of Presentation: Awaji Kokusaikaigijyo, Awaji
• [Presentation] ATF1/CREM/CREB modulates HSF1 activity during heat shock by regulating stress-inducible transcription complex formation (2013)
  • Author(s): Ryosuke Takii, Mitsuaki Fujimoto, Eiichi Takaki, Ke Tan, Ram Prakasam, Naoki Hayashida, and Akira Nakai
  • Organizer: International Symposium on Transcription and Metabolism
  • Place of Presentation: Awaji Kokusaikaigijyo, Awaji
• [Presentation] HSF1-dependent nuclear translocation of mitochondria single-strand DNA-binding protein (2013)
  • Author(s): Ke Tan, Mitsuaki Fujimoto, Ryosuke Takii, Eiichi Takaki, Ram Prakasam, Naoki Hayashida, and Akira Nakai
  • Organizer: International Symposium on Transcription and Metabolism
  • Place of Presentation: Awaji Kokusaikaigijyo, Awaji
• [Presentation] 熱ショック応答の分子機構 (2013)
  • Author(s): 中井 彰
  • Organizer: 第8回臨床ストレス応答学会 シンポジウム「 細胞ストレス応答の分子機構と疾患病態」
  • Place of Presentation: 信州大学(松本)
  • Invited
• [Presentation] ミトコンドリア一本鎖DNA結合タンパク質は熱ショック応答を促進する (2013)
  • Author(s): 譚克、藤本充章、瀧井良祐、高木栄一、Prakasam Ram、松浦優基、林田直樹、中井彰
  • Organizer: 新学術領域研究「転写代謝」若手ワークショップ
  • Place of Presentation: ホテル鬼怒川御苑 (日光)
• [Presentation] 温熱適応のしくみから迫る老化と病気 (2012)
  • Author(s): 中井 彰
  • Organizer: 温泉療法医会中国四国地方会
  • Place of Presentation: サンポートホール高松 (高松)(招待講演)
  • Year and Date: 2012-11-25
• [Presentation] Constitutive heat shock factor access to nucleosoma1 DNA regulates proteostasis capacity and tumorigenesis. (2012)
  • Author(s): Akira Nakai
  • Organizer: Mini-symposium on "Stress Signals & Responses"
  • Place of Presentation: Turku, Finland(招待講演)
  • Year and Date: 2012-09-27
• [Presentation] Heat shock factors and cancer. (2012)
  • Author(s): Akira Nakai
  • Organizer: The 11th International Congress of Hyperthermic Oncology & The 29th Japanese Congress of Thermal Medicine
  • Place of Presentation: Hayatt Regency Kyoto (Kyoto)(招待講演)
• [Presentation] Heat shock factors negatively regulate the inflammatory response. (2012)
  • Author(s): Akira Nakai, Ryosuke Takii, Naoki Hayashida, Eiichi Takaki, and Mitsuaki Fujimoto
  • Organizer: The 11th International Congress of Hyperthermic Oncology & The 29th Japanese Congress of Thermal Medicine
  • Place of Presentation: Hayatt Regency Kyoto (Kyoto)(招待講演)
• [Presentation] 熱ショック応答とがん (2012)
  • Author(s): 中井 彰
  • Organizer: 第71回日本癌学会総会
  • Place of Presentation: ロイトン札幌 (札幌)(招待講演)
• [Presentation] アノールトカゲHSF遺伝子群の分子クローニングと機能進化 (2012)
  • Author(s): 松浦優基、藤本充章、高木栄一、瀧井良祐、譚克、Prakasam Ram、伍方緒、牧野能士、河田雅圭、林田直樹、中井 彰
  • Organizer: 第35回日本分子生物学会
  • Place of Presentation: 福岡国際会議場・マリンメッセ福岡 (福岡)
• [Presentation] 熱ショック因子HSF2はWD40蛋白質と相互作用する (2012)
  • Author(s): 林田直樹、高木栄一、瀧井良祐、譚克、Prakasam Ram、松浦優基、家村俊一郎、夏目徹、藤本充章、中井 彰
  • Organizer: 第35回日本分子生物学会
  • Place of Presentation: 福岡国際会議場・マリンメッセ福岡 (福岡)
• [Presentation] 熱ショック因子HSF4のリン酸化を増強する因子の同定 (2012)
  • Author(s): 高木栄一、林田直樹、瀧井良祐、譚克、Prakasam Ram、松浦優基、家村俊一郎、夏目徹、藤本充章、中井 彰
  • Organizer: 第35回日本分子生物学会
  • Place of Presentation: 福岡国際会議場・マリンメッセ福岡 (福岡)
• [Presentation] HSF1-RPA複合体は腫瘍形成に必要である (2012)
  • Author(s): 藤本充章、高木栄一、瀧井良祐、譚克、Prakasam Ram、松浦優基、林田直樹、中井 彰
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡国際会議場・マリンメッセ福岡 (福岡)
• [Presentation] HSF1-ATF1を介するp300/CBPのリクルートはクロマチン弛緩に必要ない (2012)
  • Author(s): 瀧井良祐、藤本充章、高木栄一、譚克、Prakasam Ram、松浦優基、林田直樹、中井 彰
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡国際会議場・マリンメッセ福岡 (福岡)
• [Presentation] ミトコンドリア一本鎖DNA結合タンパク質は熱ショック応答を促進する (2012)
  • Author(s): 譚克、藤本充章、瀧井良祐、高木栄一、Prakasam Ram、松浦優基、林田直樹、中井彰
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡国際会議場・マリンメッセ福岡 (福岡)
• [Book] Analysis of the heat shock factor complex in mammalian HSP70 promoter in Methods Mol. Biol. (2015)
  • Author(s): Fujimoto M, Takii R, Hayashida N, Nakai A
  • Total Pages: 246
  • Publisher: Human Press
• [Remarks]
  • URL: http://ds22.cc.yamaguchi-u.ac.jp/-seika2
• [Patent(Industrial Property Rights)] HSF1とRPA1との相互作用阻害ペプチド (2012)
  • Inventor(s): 中井 彰、藤本充章
  • Industrial Property Rights Holder: 山口大学
  • Industrial Property Number: 2012-152395
  • Filing Date: 2012-07-06