Mechanisms of pancreatic beta-cell tumorigenesis by tumor suppressor function failure of tumor suppressor gene MEN1.

• Project/Area Number: 26461374
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Endocrinology
• Research Institution: Gunma University
• Principal Investigator: OZAWA ATSUSHI 群馬大学, 大学院医学系研究科, 助教 (10573496)
• Co-Investigator(Renkei-kenkyūsha): YAMADA Masanobu 群馬大学, 大学院・医学系研究科, 教授 (90261833)
• Research Collaborator: WATANABE Takuya
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 遺伝子 / 内分泌腫瘍 / 遺伝性腫瘍 / 腫瘍症候群 / 遺伝子改変動物 / 多発性内分泌腫瘍症１型 / インスリノーマ / 膵内分泌腫瘍 / 遺伝性腫瘍症 / 癌抑制遺伝子

Outline of Final Research Achievements

The mechanisms of tumorigenesis of pancreatic-neuroendocrine tumor (p-NET) is still unclear. Several genes were reported to be involved in the tumorigensis pathway of p-NET. Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominantly inherited syndrome characterized by the occurrence of tumors in pituitary, parathyroid and enteropancreatic neuroendocrine glands. It is known that JunD is one of the main binding partners of menin encoded by MEN1 gene. We generated and analyzed the transgenic mice that over-expressed mutant JunD. We investigated that this mouse cold be the model of insulinoma. The mechanisms underlying the tumorigensis of this mouse was different from the previous reports revealing the p-NET tumorigensis.

Research Products

• [Journal Article] Fyn phosphorylates AMPK to inhibit AMPK activity and AMP-dependent activation of autophagy. (2016)
  • Author(s): Yamada E, Okada S, Bastie CC, Vatish M, Nakajima Y, Shibusawa R, Ozawa A, Pessin JE, Yamada M.
  • Journal Title: Oncotarget Volume: 7 Issue: 46 Pages: 74612-74629
  • DOI: 10.18632/oncotarget.11916
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] APPL1 promotes glucose uptake in response to mechanical stretch via the PKCζ-non-muscle myosin IIa pathway in C2C12 myotubes. (2016)
  • Author(s): Saito T, Okada S, Shimoda Y, Tagaya Y, Osaki A, Yamada E, Shibusawa R, Nakajima Y, Ozawa A, Satoh T, Mori M, Yamada M
  • Journal Title: Cell Signal Volume: 28 Issue: 11 Pages: 1694-1702
  • DOI: 10.1016/j.cellsig.2016.07.010
  • Peer Reviewed / Open Access
• [Journal Article] Effect of carbohydrate counting using bolus calculators on glycemic control in type 1 diabetes patients during continuous subcutaneous insulin infusion. (2016)
  • Author(s): Yamada E, Okada S, Nakajima Y, Bastie CC, Tagaya Y, Osaki A, Shimoda Y, Shibusawa R, Saito T, Ozawa A, Yamada M.
  • Journal Title: Journal of Diabetes Investigations Volume: - Issue: 4 Pages: 496-500
  • DOI: 10.1111/jdi.12604
  • Peer Reviewed
• [Journal Article] GNAS mutations in adrenal aldosterone-producing adenomas. (2016)
  • Author(s): Nakajima Y, Okamura T, Horiguchi K, Gohko T, Miyamoto T, Satoh T, Ozawa A, Ishii S, Yamada E, Hashimoto K, Okada S, Takata D, Horiguchi J, Yamada M.
  • Journal Title: Endocrine Journal Volume: 63 Pages: 199-204
  • Peer Reviewed
• [Journal Article] Reversible Hypopituitarism Associated with Intravascular Large B-Cell Lymphoma: Case Report of Successful Immunochemotherapy. (2016)
  • Author(s): Sawada Y, Ishii S, Koga Y, Tomizawa T, Matsui A, Tomaru T, Ozawa A, Shibusawa N, Satoh T, Shimizu H, Hirato J, Yamada M.
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 238 Pages: 197-203
  • NAID: 130005131608
  • Peer Reviewed
• [Journal Article] Somatic mutations of the catalytic subunit of cyclic AMP-dependent protein kinase (PRKACA) gene in Japanese patients with several adrenal adenomas secreting cortisol. (2014)
  • Author(s): Nakajima Y, Okamura T, Gohko T, Satoh T, Hashimoto K, Shibusawa N, Ozawa A, Ishii S, Tomaru T, Horiguchi K, Okada S, Takata D, Rokutanda N, Horiguchi J, Tsushima Y, Oyama T, Takeyoshi I, Yamada M.
  • Journal Title: Endocr J Volume: 61 Pages: 825-832
  • Peer Reviewed
• [Journal Article] Coordinated regulation of transcription and alternative splicing by the thyroid hormone receptor and its associating coregulators. (2014)
  • Author(s): Satoh T, Katano-Toki A, Tomaru T, Yoshino S, Ishizuka T, Horiguchi K, Nakajima Y, Ishii S, Ozawa A, Shibusawa N, Hashimoto K, Mori M, Yamada M.
  • Journal Title: Biochem Biophys Res Commun Volume: 451 Issue: 1 Pages: 21-29
  • DOI: 10.1016/j.bbrc.2014.07.029
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Protection against high-fat diet-induced obesity in Helz2-deficient male mice due to enhanced expression of hepatic leptin receptor (2014)
  • Author(s): Yoshino S, Satoh T, Yamada M, Hashimoto K, Tomaru T, Katano-Toki A, Kakizaki S, Okada S, Shimizu H, Ozawa A, Tuchiya T, Ikota H, Nakazato Y, Mori M, Matozaki T, Sasaki T, Kitamura T, Mori M.
  • Journal Title: Endocrinology. Volume: 155 Issue: 9 Pages: 3459-3472
  • DOI: 10.1210/en.2013-2160
  • Peer Reviewed
• [Journal Article] A case of thyroid storm with a markedly elevated level of circulating soluble interleukin-2 receptor complicated by multiple organ failure and disseminated intravascular coagulation syndrome. (2014)
  • Author(s): Shimoda Y, Satoh T, Takahashi H, Katano-Toki A, Ozawa A, Tomaru T, Horiguchi N, Kaira K, Nishioka M, Shibusawa N, Hashimoto K, Wakino S, Mori M, Yamada M.
  • Journal Title: Endocr J Volume: 61 Pages: 691-696
  • NAID: 130004677940
  • Peer Reviewed
• [Presentation] 癌抑制蛋白meninの膵ラ氏島細胞における機能解析 (2017)
  • Author(s): 小澤厚志、渡邉琢也、堀口和彦、松本俊一、吉野聡、中島康代、登丸琢也、石井角保、渋沢信行、岡田秀一、佐藤哲郎、山田正信
  • Organizer: 第９０日本内分泌学会学術総会
  • Place of Presentation: 京都
  • Year and Date: 2017-04-20
• [Presentation] Roles of Thyrotropin-Releasing Hormone (TRH) during Cold Exposure and Fasting. (2017)
  • Author(s): Atsushi Ozawa, Takuya Watanabe, Takuya Tomaru, Sumiyasu Ishii, Nobuyuki Shibusawa, Tetsurou Satoh, Masanobu Yamada
  • Organizer: 12th Asia and Oceania Thyroid Association (AOTA) Congress
  • Place of Presentation: 釜山、韓国
  • Year and Date: 2017-03-16
  • Int'l Joint Research
• [Presentation] 遺伝性腫瘍症候群において発症する機能性下垂体腺腫の診断と治療 (2017)
  • Author(s): 小澤厚志、佐藤哲郎、登坂雅彦、山田正信
  • Organizer: 第２７回間脳下垂体腫瘍学会
  • Place of Presentation: 東京
  • Year and Date: 2017-02-24
  • Invited
• [Presentation] 癌抑制蛋白meninと転写因子JunDの共役結合破綻による膵β細胞腫瘍発症機構のin-vivo解析 (2016)
  • Author(s): 小澤厚志、渡邉琢也、渋沢信行、岡田秀一、佐藤哲郎、山田正信
  • Organizer: 第５９回日本糖尿病学会年次学術集会
  • Place of Presentation: 京都
  • Year and Date: 2016-05-19
• [Presentation] 癌抑制遺伝子MEN1の膵β細胞における機能解析 (2016)
  • Author(s): 小澤厚志、渡邉琢也、堀口和彦、登丸琢也、石井角保、渋沢信行、岡田秀一、佐藤哲郎、山田正信
  • Organizer: 第８９日本内分泌学会学術総会
  • Place of Presentation: 京都
  • Year and Date: 2016-04-21
• [Presentation] ヒト多発性内分泌腫瘍症１型（MEN1）遺伝子は下垂体腺腫組織型によってsplicing variantの発現様式が異なる (2016)
  • Author(s): 小澤厚志
  • Organizer: 第26回 日本間脳下垂体腫瘍学会
  • Place of Presentation: 福島県、福島市
  • Year and Date: 2016-02-19
  • Invited
• [Presentation] Thyrotropin-Releasing Hormone (TRH) Regulates Cold-Induced Adaptive Thermogenesis in Brown Adipose Tissue. (2015)
  • Author(s): Ozawa A, Watanabe T, Tomaru T, Ishii S, Shibusawa N, Mori M, Satoh T, Yamada M.
  • Organizer: 15th International Thyroid Congress and 85th Annual Meeting of the ATA (American Thyroid Association).
  • Place of Presentation: Orlando, FL, USA.
  • Year and Date: 2015-10-18
  • Int'l Joint Research
• [Presentation] 癌抑制蛋白meninと転写因子JunDの共役結合破綻が膵神経内分泌細胞に与える影響 (2015)
  • Author(s): 小澤厚志、渡邉琢也、堀口和彦、松本俊一、登丸琢也、石井角保、渋沢信行、岡田秀一、佐藤哲郎、山田正信
  • Organizer: 第42回 日本神経内分泌学会
  • Place of Presentation: 宮城県、仙台市
  • Year and Date: 2015-09-18
• [Presentation] Role of menin in the proliferation and differentiation of pancreatic beta cells （シンポジウム） (2015)
  • Author(s): Ozawa A, Watanabe T, Okada S, Satoh T, Yamada M
  • Organizer: 第５８回日本糖尿病学会年次学術集会
  • Place of Presentation: 下関
  • Year and Date: 2015-05-21 – 2015-05-24
• [Presentation] Role of menin in the proliferation and differentiation of pancreatic beta cells. (2015)
  • Author(s): Atsushi Ozawa，Takuya Watanabe，Shuichi Okada，Tetsurou Satoh，Masanobu Yamada
  • Organizer: 第58回 日本糖尿病学会年次学術集会
  • Place of Presentation: 山口県、下関市
  • Year and Date: 2015-05-21
• [Presentation] 膵β細胞におけるmeninの機能解析 (2015)
  • Author(s): 小澤厚志、渡邉琢也、堀口和彦、松本俊一、中島康代、登丸琢也、石井角保、渋沢信行、岡田秀一、佐藤哲郎、山田正信
  • Organizer: 第８８回日本内分泌学会学術総会
  • Place of Presentation: 東京
  • Year and Date: 2015-04-23 – 2015-04-25
• [Presentation] 膵β細胞におけるmeninの機能解析 (2015)
  • Author(s): 小澤厚志、渡邉琢也、堀口和彦、松本俊一、中島康代、登丸琢也、石井角保、渋沢信行、岡田秀一、佐藤哲郎、山田正信
  • Organizer: 第88回 日本内分泌学会学術総会
  • Place of Presentation: 東京都、東京
  • Year and Date: 2015-04-23
• [Presentation] ヒト多発性内分泌腫瘍症１型（MEN1）遺伝子は下垂体腺腫組織型によってsplicing variantの発現様式が異なる (2015)
  • Author(s): 小澤厚志
  • Organizer: 第２５回日本間脳下垂体腫瘍学会
  • Place of Presentation: 京都
  • Year and Date: 2015-02-27 – 2015-02-28
  • Invited
• [Presentation] 多発性内分泌腫瘍症１型（MEN1）における膵内分泌腫瘍発症機構：モデルマウスを用いたマイクロアレイ解析 (2014)
  • Author(s): 小澤厚志、渡邉琢也、登丸琢也、石井角保、渋沢信行、岡田秀一、佐藤哲郎、山田正信
  • Organizer: 第５９回日本人類遺伝学会
  • Place of Presentation: 東京
  • Year and Date: 2014-11-19 – 2014-11-22
• [Presentation] 多発性内分泌腫瘍症１型（MEN1）モデルマウスにおけるcDNAマイクロアレイ解析 (2014)
  • Author(s): 小澤厚志、渡邉琢也、堀口和彦、松本俊一、中島康代、登丸琢也、石井角保、渋沢信行、岡田秀一、佐藤哲郎、山田正信
  • Organizer: 第４１回日本神経内分泌学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] ラ氏島の腫瘍化機構におけるmenin-JunD共役結合の役割：モデルマウスの樹立とマイクロアレイ解析 (2014)
  • Author(s): 小澤厚志、渡邉琢也、中島康代、登丸琢也、石井角保、渋沢信行、岡田秀一、森 昌朋、佐藤哲郎、山田正信
  • Organizer: 第５７回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-05-22 – 2014-05-24
• [Presentation] ヒト下垂体腺腫における多発性内分泌腫瘍症１型（MEN1）遺伝子Splicing variantの発現解析 (2014)
  • Author(s): 小澤厚志、渡邉琢也、登坂雅彦、好本裕平、土岐明子、中島康代、登丸琢也、石井角保、渋沢信行、橋本貢士、岡田秀一、佐藤哲郎、山田正三、森 昌朋、山田正信
  • Organizer: 第８７回日本内分泌学会学術総会
  • Place of Presentation: 福岡
  • Year and Date: 2014-04-24 – 2014-04-26
• [Book] 臨床画像「Tumor syndrome」 (2015)
  • Author(s): 小澤厚志、山田正信
  • Total Pages: 3
  • Publisher: メジカルビュー社