Mechanisms and applications of SIK2-regulation for neuro-protection

2013 Fiscal Year Final Research Report

• Project/Area Number: 23390082
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: 独立行政法人医薬基盤研究所
• Principal Investigator: TAKEMORI Hiroshi 独立行政法人医薬基盤研究所, 創薬基盤研究部, プロジェクトリーダー (90273672)
• Co-Investigator(Kenkyū-buntansha): HATANO Osamu 奈良県立医科大学, 医学部, 講師 (40164850) ; KITAGAWA Kazuo 大阪大学, 医学系研究科, 准教授 (70301257) ; NAGAOKA Yasuo 関西大学, 工学部, 教授 (90243039)
• Co-Investigator(Renkei-kenkyūsha): KUMAGAI Ayako 独立行政法人医薬基盤研究所, 創薬基盤研究部, 特任研究員 (20455869)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Keywords: SIK / CREB / 転写 / 神経保護 / フラボノイド

Research Abstract

We reported that SIK2-KO mice showed neuro-protective phenotypes after the ischemia-reperfusion operation. In addition, SIK2 regulates hair color by inhibiting melanogenesis. By using these phenotypes, we tried to indentify new compounds that are helpful to care ischemia-reperfusion damage in the brain. We screened compounds by an in vitro kinase assay and identified fisetin as a candidate for the SIK2 inhibitor. However, fisetin did not inhibit SIK2 actions in cultured cells. Interestingly, fisetin changed mouse hair color, and we found methoxy-fisetin in mouse feces. The synthesized methoxy-fisetin (4MF) inhibited SIK2 and acted as a neuro-protector after the glutamate treatment in primary neurons. 4MF-treated mice showed enhanced memory capacity. In addition to 4MF, we obtained some compounds that showed neuro-protective activities in an SIK2 dependent or independent manners.

Research Products

• [Journal Article] Prostaglandin E promotes Th1 differentiation via synergistic amplification of IL-12 signalling by cAMP and PI3-kinase (2013)
  • Author(s): Yao C, Hirata T, Soontrapa K, Ma X, Takemori H, Narumiya S
  • Journal Title: Nat Commun Volume: 4 Pages: 1685
• [Journal Article] LKB1 tumor suppressor and salt-inducible kinases negatively regulate human T-cell leukemia virus type 1 transcription (2013)
  • Author(s): Tang HM, Gao WW, Chan CP, Siu YT, Wong CM, Kok KH, Ching YP, Takemori H, Jin DY
  • Journal Title: Retrovirology Volume: 10 Pages: 40
• [Journal Article] Induction of melanogenesis by 4'-O-methylated flavonoids in B16F10 melanoma cells (2013)
  • Author(s): Horibe I, Satoh Y, Shiota Y, Kumagai A, Horike N, Takemori H, Uesato S, Sugie S, Obata K, Kawahara H, Nagaoka Y
  • Journal Title: J Nat Med Volume: 67 Pages: 705-10
• [Journal Article] Salt-inducible kinase 1 is involved in high glucose-induced mesangial cell proliferation mediated by the ALK5 signaling pathway (2013)
  • Author(s): Yu J, Hu X, Yang Z, Takemori H, Li Y, Zheng H, Hong S, Liao Q, Wen X
  • Journal Title: Int J Mol Med Volume: 32 Pages: 151-157
• [Journal Article] 注目される病態関連分子 AMPK 分子脳血管学 (2013)
  • Author(s): 伊東祐美, 竹森 洋
  • Volume: 12
  • Pages: 54-58
• [Journal Article] Involvement of SIK3 in glucose and lipid homeostasis in mice (2012)
  • Author(s): Uebi T, Itoh Y, Hatano O, Kumagai A, Sanosaka M, Sasaki T, Sasagawa S, Doi J, Tatsumi K, Mitamura K, Morii E, Aozasa K, Kawamura T, Okumura M, Nakae J, Takikawa H, Fukusato T, Koura M, Nish M, Hamsten A, Silveira A, Bertorello AM, Kitagawa K, Nagaoka Y, Kawahara H, Tomonaga T, Naka T, Ikegawa S, Tsumaki N, Matsuda J, Takemori H
  • Journal Title: PLoS One Volume: 7 Pages: e37803
  • Peer Reviewed
• [Journal Article] Novel repressor regulates insulin sensitivity through interaction with Foxo1 (2012)
  • Author(s): Nakae J, Cao Y, Hakuno F, Takemori H, Kawano Y, Sekioka R, Abe T, Kiyonari H, Tanaka T, Sakai J, Takahashi S, Itoh H
  • Journal Title: EMBO J Volume: 31 Pages: 2275-95
• [Journal Article] Increases in intracellular sodium activate transcription and gene expression via the salt-inducible kinase 1 network in an atrial myocyte cell line (2012)
  • Author(s): Popov S, Venetsanou K, Chedrese PJ, Pinto V, Takemori H, Franco-Cereceda A, Eriksson P, Mochizuki N, Soares-da-Silva P, Bertorello AM
  • Journal Title: Am J Physiol Heart Circ Physiol Volume: 303 Pages: H57-65
• [Journal Article] SIK3 is essential for chondrocyte hypertrophy during skeletal development in mice (2012)
  • Author(s): Sasagawa S, Takemori H, Uebi T, Ikegami D, Hiramatsu K, Ikegawa S, Yoshikawa H, Tsumaki N
  • Journal Title: Development Volume: 139 Pages: 1153-63
• [Journal Article] Salt-inducible kinase is involved in the regulation of corticotropin-releasing hormone transcription in hypothalamic neurons in rats (2012)
  • Author(s): Liu Y, Poon V, Sanchez-Watts G, Watts AG, Takemori H, Aguilera G
  • Journal Title: Endocrinology Volume: 153 Pages: 223-33
• [Journal Article] Cocaine induces the expression of MEF2C transcription factor in rat striatum through activation of SIK1 and phosphorylation of the histone deacetylase HDAC5 (2012)
  • Author(s): Dietrich JB, Takemori H, Grosch-Dirrig S, Bertorello A, Zwiller J
  • Journal Title: Synapse Volume: 66 Pages: 61-70
• [Journal Article] cAMP stimulation of STAR expression and cholesterol metabolism (2011)
  • Author(s): Jefcoate CR, Lee J, Cherradi N, Takemori H
  • Journal Title: Mol Cell Endocrinol Volume: 336 Pages: 53-62
• [Journal Article] Salt-inducible kinase 1 influences Na(+),K(+)-ATPase activity in vascular smooth muscle cells and associates with variations in blood pressure (2011)
  • Author(s): Popov S, Silveira A, Wågsäter D, Takemori H, Oguro R, Matsumoto S, Sugimoto K, Kamide K, Hirose T, Satoh M, Metoki H, Kikuya M, Ohkubo T, Katsuya T, Rakugi H, Imai Y, Sanchez F, Leosdottir M, Syvänen AC, Hamsten A, Melander O, Bertorello AM
  • Journal Title: J Hypertens Volume: 29 Pages: 2395-403
• [Journal Article] A potent inhibitor of SIK2, 3, 3', 7-trihydroxy-4'-methoxyflavon (4'-O-methylfisetin), promotes melanogenesis in B16F10 melanoma cells (2011)
  • Author(s): Kumagai A, Horike N, Satoh Y, Uebi T, Sasaki T, Itoh Y, Hirata Y, Uchio-Yamada K, Kitagawa K, Uesato S, Kawahara H, Takemori H Nagaoka Y
  • Journal Title: PLoS One Volume: 6 Pages: e26148
• [Journal Article] Carbohydrate metabolism is perturbed in peroxisome-deficient hepatocytes due to mitochondrial dysfunction, AMP-activated protein kinase (AMPK) activation, and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) suppression (2011)
  • Author(s): Peeters A, Fraisl P, van den Berg S, Ver Loren van Themaat E, Van Kampen A, Rider MH, Takemori H, van Dijk KW, Van Veldhoven PP, Carmeliet P, Baes M
  • Journal Title: J Biol Chem Volume: 286 Pages: 42162-79
• [Journal Article] Salt-inducible kinase 1 is present in lung alveolar epithelial cells and regulates active sodium transport (2011)
  • Author(s): Eneling K, Chen J, Welch LC, Takemori H, Sznajder JI, Bertorello AM
  • Journal Title: Biochem Biophys Res Commun Volume: 409 Pages: 28-33
• [Presentation] カルノソール・カルノソール誘導体による酸化ストレスに対する臓器保護 (2013)
  • Author(s): 川村知裕,舟木壮一郎,中桐伴行,新谷康,井上匡美,澤端章好,南 正人,杉村康司,飯田修,渕野裕之,川原信夫,竹森洋,奥村明之進
  • Organizer: 第194回近畿外科学会
  • Place of Presentation: 大阪
  • Year and Date: 2013-11-09
• [Presentation] Effects of Pterosin B from Pteridium Aquilinum on the blood glucose level in db/db mice (2013)
  • Author(s): Ito Y, Sanosaka M, Kumagai A, Takemori H, Fuchino H, Kawahara N, Doi J, Ota M
  • Organizer: The EMBO meeting
  • Place of Presentation: AMSETDAM
  • Year and Date: 2013-09-22
• [Presentation] SIK3 によるクラスII-HDAC 制御がコレステロール-胆汁酸代謝へ与える影響 (2012)
  • Author(s): 伊東祐美,佐野坂真人,熊谷彩子,竹森洋
  • Organizer: 第85回日本生化学会
  • Place of Presentation: 福岡
  • Year and Date: 2012-12-16
• [Presentation] 塩誘導性キナーゼ 2 (SIK2)の新規メラニン合成調節機構について (2012)
  • Author(s): 熊谷彩子,堀家なな緒,伊東祐美,長岡康夫,竹森 洋
  • Organizer: 第85回日本生化学会
  • Place of Presentation: 福岡
  • Year and Date: 2012-12-16
• [Presentation] SIK3 はマクロファージにおける炎症性サイトカインの発現を制御する (2012)
  • Author(s): 佐野坂真人,伊東祐美,藤本穣,大河原知治,仲哲治,竹森 洋
  • Organizer: 第85回日本生化学会
  • Place of Presentation: 福岡
  • Year and Date: 2012-12-16
• [Presentation] ニコチンによる CREB-CRTC 活性化を介した神 経保護機構の検討 (2012)
  • Author(s): 佐々木勉, 竹森 洋,大山直紀,由上登志郎,渡邊彰弘,八木田佳樹,望月秀樹,北川一夫
  • Organizer: 第24回日本脳循環代謝学会
  • Place of Presentation: 広島
  • Year and Date: 2012-11-08
• [Presentation] 新たなエノキ素材による体重減少と胆汁酸代謝亢進作用について (2012)
  • Author(s): 伊東祐美,大西智子,田村淑恵,藤川和平,土居純子,竹森 洋,片倉啓雄,河原秀久
  • Organizer: 第51回日本栄養・食糧学会 近畿支部大会
  • Place of Presentation: 宝塚
  • Year and Date: 2012-10-20
• [Presentation] 植物由来フラボノイド A に新規に見出されたかん細胞優位な放射線増感作用 (2012)
  • Author(s): 坂東真一,秦野 修,竹森 洋,窪田宜夫,大西健
  • Organizer: 第71回日本癌学会
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-20
• [Presentation] フ ラ ボ ノ イ ド 3,5,7-Trihydroxy-3,4 ' -Dimethoxyflavone に新規に見出されたがん細胞優位な細胞致死作用 (2012)
  • Author(s): 大西健,坂東真一,秦野 修,竹森 洋,窪田宜夫
  • Organizer: 第71回日本癌学会
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-20
• [Presentation] GPCR を介した神経活動依存的な遺伝子発現制御に関する解析 (2012)
  • Author(s): 津田正明,福地守,桑名由紀,井上南,越智雄基,市村美奈,高崎一朗,竹森 洋,田渕明子
  • Organizer: 第35回日本神経科学会
  • Place of Presentation: 名古屋
  • Year and Date: 2012-09-18
• [Presentation] ニコチンによる神経保護効果におけるCREB-CRTC シクナルの意義 (2012)
  • Author(s): 佐々木勉,北川一夫,寺崎泰和,大山直紀,杉山幸生,八木田佳樹,竹森 洋,望月秀樹
  • Organizer: 第35回日本神経科学会
  • Place of Presentation: 名古屋
  • Year and Date: 2012-09-18
• [Presentation] 塩誘導性キナーセ SIK3 はコレステロール,胆汁酸代謝に重要である (2012)
  • Author(s): 伊東祐美,上尾達也,熊谷彩子,竹森 洋,土居純子
  • Organizer: 第66回日本栄養食料学会
  • Place of Presentation: 仙台
  • Year and Date: 2012-05-19
• [Patent(Industrial Property Rights)] カスパーゼ 1 活性化阻害剤,抗炎症剤,鎮痒剤,及びカスパーゼ1活性化阻害剤の評価方法 (2013)
  • Inventor(s): 竹森 洋, 佐野坂真人, 伊東祐美, 渕野裕之, 川原信夫
  • Industrial Property Rights Holder: 独立行政法人医薬基盤研究所,株式会社桃谷順天館
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-094995
  • Filing Date: 2013-04-30
• [Patent(Industrial Property Rights)] プテロシン誘導体を含む軟骨変性,および/または軟骨菲薄疾患治療剤 (2013)
  • Inventor(s): 妻木範行, 竹森 洋, 渕野裕之, 川原信夫
  • Industrial Property Rights Holder: 国立大学法人京都大学, 独立行政法人医薬基盤研究所
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-135040
  • Filing Date: 2013-06-27
• [Patent(Industrial Property Rights)] チロシナーゼ誘導抑制剤及びメラニン合成抑制剤 (2012)
  • Inventor(s): 竹森 洋, 熊谷彩子, 森田純子, 渕野裕之, 川原信夫, 飯田 修, 杉村康司, 志賀幸生, 鎌田 文広, 香月茂樹, 河原秀久, 長岡康夫
  • Industrial Property Rights Holder: 株式会社桃谷順天館
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2012-249917
  • Filing Date: 2012-11-24
• [Patent(Industrial Property Rights)] PPARd 活性化剤および PPARd 活性化剤の製造方法 (2011)
  • Inventor(s): 河原秀久, 長岡康夫, 竹森 洋, 小出芳栄
  • Industrial Property Rights Holder: 学校法人関西大学,独立行政法人医薬基盤研究所,有限会社一栄
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2011-250865
  • Filing Date: 2011-11-16