Molecular mechanisms of tumorigeneis in multiple endocrine neoplasia type 1 (MEN)

• Project/Area Number: 23591346
• 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, 医学部附属病院, 助教 (10573496)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 内分泌学 / 内分泌腫瘍 / 遺伝性腫瘍症 / 遺伝性疾患 / 膵ラ氏島 / 多発性内分泌腫瘍症１型 / MEN1 / 癌抑制遺伝子 / 膵内分泌腫瘍 / 多発性内分泌腫瘍症

Research Abstract

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominantly inherited syndrome characterized by the occurrence of tumors in multiple endocrine tissues including parathyroid, enteropancreatic neuroendocrine and anterior pituitary. Although the tissue selectivity of tumors in specific endocrine organs is the essence of MEN1, the mechanisms underlying the tissue-specific tumorigenesis remain unknown. It is known that JunD and MLL, both transcription factors, are main binding partners of menin encoded by MEN1 gene. Through the analysis of mouse models and cDNA microarray, we investigated that JunD and MLL are the key molecules in tumorigenesis of endocrine tissues in MEN1.

Research Products

• [Journal Article] THRAP3 interacts with HELZ2 and plays a novel role in adipocyte differentiation. (2013)
  • Author(s): Katano-Toki A, Satoh T, Tomaru T, Yoshino S, Ishizuka T, Ishii S, Ozawa A, Shibusawa N, Tsuchiya T, Saito T, Shimizu H, Hashimoto K, Okada S, Yamada M, Mori M
  • Journal Title: Molecular Endocrinology Volume: 27 Issue: 5 Pages: 769-780
  • DOI: 10.1210/me.2012-1332
  • Peer Reviewed
• [Journal Article] Humna stearoyl-CoA desaturase 1 (SCD-1) gene expression is negatively regulated by thyroid hormone without direct binding of thyroid hormone receptor to the gene promoter. (2013)
  • Author(s): Hashimoto K
  • Journal Title: Endocrinology Volume: 154 Issue: 1 Pages: 537-549
  • DOI: 10.1210/en.2012-1559
  • Peer Reviewed
• [Journal Article] KCNJ5 mutations in aldosterone- and cortisol-co-secreting adrenal adenomas (2012)
  • Author(s): Yamada M, Nakajima Y, Ozawa A, Mori M
  • Journal Title: Endocr J Volume: 59 Pages: 735-741
  • NAID: 10031064823
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/22863749
  • Peer Reviewed
• [Journal Article] NR4A1 (Nur77) mediates thyrotropin-releasing hormone-induced stimulation of transcription of the thyrotropin β gene: analysis of TRH knockout mice. (2012)
  • Author(s): Nakajima Y
  • Journal Title: PLos One Volume: 7 Issue: 7 Pages: e40437-e40437
  • DOI: 10.1371/journal.pone.0040437
  • Peer Reviewed
• [Journal Article] Expression of mutations of KCNJ5 mRNA in Japanese patients with aldosterone-producing adenomas. (2012)
  • Author(s): Taguchi R
  • Journal Title: J Clin Endocrinol Metab Volume: 97 Issue: 4 Pages: 1311-1319
  • DOI: 10.1210/jc.2011-2885
  • Peer Reviewed
• [Journal Article] Multiple Endocrine Neoplasia Type 1in Japan : Establishment and Analysis of a Multicenter Database (2012)
  • Author(s): Sakurai, Akihiro ; Suzuki, Shinichi ; Kosugi, Shinji ; Okamoto, Takahiro ; Uchino, Shinya ; Miya, Akihiro ; Imai, Tsuneo ; Kaji, Hiroshi ; Komoto, Izumi ; Miura, Daishu ; Yamada, Masanobu ; Uruno, Takashi ; Horiuchi, Kiyomi
  • Journal Title: European Review for Medical and Pharmacological Sciences Volume: 76(4) Issue: 4 Pages: 533-539
  • DOI: 10.1111/j.1365-2265.2011.04227.x
  • Peer Reviewed
• [Journal Article] Delay in the diagnosis of multiple endocrine neoplasia type 1: typical symptoms are frequently overlooked. (2012)
  • Author(s): Yamazaki M, Suzuki S, Kosugi S, Uchino S, Miura D, Yamada M, Miyauchi A, Imamura M, Sakurai A; MEN Consortium of Japan et al
  • Journal Title: Endocr J Volume: 59 Pages: 797-807
  • Peer Reviewed
• [Journal Article] KCNJ5 mutations in aldosterone- and cortisol-co-secreting adrenal adenomas. (2012)
  • Author(s): Yamada M, Nakajima Y, Taguchi R, Okamura T, Ishii S, Tomaru T, Ozawa A, Shibusawa N, Yoshino S, Toki A, Ishida E, Hashimoto K, Satoh T, Mori M.
  • Journal Title: Endocr J Volume: 59 Pages: 735-741
  • NAID: 10031064823
  • Peer Reviewed
• [Journal Article] The tumor suppressor protein menin inhibits AKT activation by regulating its cellular localization (2011)
  • Author(s): Wang Y, Ozawa A, Marx SJ
  • Journal Title: Cancer Res Volume: 71 Issue: 2 Pages: 371-382
  • DOI: 10.1158/0008-5472.can-10-3221
  • Peer Reviewed
• [Journal Article] Haploinsufficient and Predominant Expression of Multiple Endocrine Neoplasia Type 1 (MEN1)-Related Genes, MLL, p27^<Kip1>and p18^<Ink4C>in Endocrine Organs (2011)
  • Author(s): Taguchi R, Yamada M, Horiguchi K, Ozawa A, Shibusawa N, Hashimoto K, Satoh T, Mori M
  • Journal Title: Biochem Biophys Res Commun Volume: 415 Issue: 2 Pages: 378-383
  • DOI: 10.1016/j.bbrc.2011.10.077
  • Peer Reviewed
• [Journal Article] Cardiovascular complications of patients with aldosteronism associated with autonomous cortisol secretion (2011)
  • Author(s): Nakajima Y, Yamada M, Taguchi R, Satoh T, Hashimoto K, Ozawa A, Shibusawa N, Okada S, Monden T, Mori M
  • Journal Title: J Clin Endocrinol Metab Volume: 96 Issue: 8 Pages: 2512-2518
  • DOI: 10.1210/jc.2010-2743
  • Peer Reviewed
• [Journal Article] Attenuated expression of menin and p27 (Kip1) in an aggressive case of multiple endocrine neoplasia type 1 (MEN1) associated with an atypical prolactinoma and a malignant pancreatic endocrine tumor (2011)
  • Author(s): Ishida E, Ozawa A, Mori M
  • Journal Title: Endocr J Volume: 58 Pages: 287-96
  • NAID: 130004443685
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/21441703
  • Peer Reviewed
• [Journal Article] Liver X receptor-α/βexpression ratio is increased in ACTH-secreting pituitary adenomas (2011)
  • Author(s): Hashimoto K, Matsumoto S, Ishida E, Miura A, Horiguchi K, Ozawa A, Shibusawa N, Satoh T, Yamada M, Yamada S, Mori M
  • Journal Title: Neurosci Lett Volume: 494 Issue: 1 Pages: 34-37
  • DOI: 10.1016/j.neulet.2011.02.048
  • Peer Reviewed
• [Journal Article] Haploinsufficient and predominant expression of multiple endocrine neoplasia type 1 (MEN1)-related genes, MLL, p27Kip1 and p18Ink4C in endocrine organs. (2011)
  • Author(s): Taguchi R, Yamada M, Horiguchi K, Tomaru T, Ozawa A, Shibusawa N, Hashimoto K, Okada S, Satoh T, Mori M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 415 Pages: 378-383
  • Peer Reviewed
• [Journal Article] Cardiovascular complications of patients with aldosteronism associated with autonomous cortisol secretion. (2011)
  • Author(s): Nakajima Y, Yamada M, Taguchi R, Satoh T, Hashimoto K, Ozawa A, Shibusawa N, Okada S, Monden T, Mori M.
  • Journal Title: J Clin Endocrinol Metab. Volume: 96 Pages: 2512-2518
  • Peer Reviewed
• [Journal Article] Attenuated expression of menin and p27 (Kip1) in an aggressive case of multiple endocrine neoplasia type 1 (MEN1) associated with an atypical prolactinoma and a malignant pancreatic endocrine tumor. (2011)
  • Author(s): Ishida E, Yamada M, Horiguchi K, Taguchi R, Ozawa A, Shibusawa N, Hashimoto K, Satoh T, Yoshida S, Tanaka Y, Yokota M, Tosaka M, Hirato J, Yamada S, Yoshimoto Y, Mori M.
  • Journal Title: Endocr J. Volume: 58 Pages: 287-296
  • NAID: 130004443685
  • Peer Reviewed
• [Journal Article] Liver X receptor-α/β expression ratio is increased in ACTH-secreting pituitary adenomas. (2011)
  • Author(s): Hashimoto K, Matsumoto S, Ishida E, Miura A, Horiguchi K, Ozawa A, Shibusawa N, Satoh T, Yamada M, Yamada S, Mori M.
  • Journal Title: Neurosci Lett. Volume: 494 Pages: 34-37
  • Peer Reviewed
• [Journal Article] 多発性内分泌腫瘍の病態生理と臨床像 (2011)
  • Author(s): 小澤厚志, 山田正信
  • Journal Title: 日本臨床 Volume: 69巻増刊2 Pages: 681-685
• [Presentation] Distinct expression of splicing variants of the human MEN1 (multiple endocrine neoplasia type 1) gene in various pituitary adenomas (2014)
  • Author(s): Atsushi Ozawa, Takuya Watanabe 他
  • Organizer: 11^<th> Annual ENETS (European neuroendocrine tumor society) conference
  • Place of Presentation: バルセロナ、スペイン
• [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、佐藤哲郎、中島康代、登丸琢也、石井角保、渋沢信行、岡田秀一、森 昌朋、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
• [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抄録集
  • Place of Presentation: 福岡
• [Presentation] Distinct expression of splicing variants of the human MEN1 (multiple endocrine neoplasia type 1) gene in various pituitary adenomas. (2014)
  • Author(s): Atsushi Ozawa, Takuya Watanabe, Masahiko Tosaka, Yuhei Yoshimoto, Kazuhiko Horiguchi, Yasuyo Nakajima, Takuya Tomaru, Sumiyasu Ishii, Nobuyuki Shibusawa, Shuichi Okada, Tetsurou Satoh, Masanobu Yamada.
  • Organizer: 11th Annual ENETS (European neuroendocrine tumor society) conference.
  • Place of Presentation: バルセロナ、スペイン
• [Presentation] 変異JunDによる膵神経内分泌腫瘍発症機構の解明:膵β細胞特異的変異JunDトランスジェニックマウスの作製と解析 (2013)
  • Author(s): 小澤厚志、渡邉琢也 他
  • Organizer: 第40回日本神経内分泌学会学術集会
  • Place of Presentation: 宮崎
• [Presentation] MEN1遺伝子Exon1 splicing variantの腫瘍組織における発現解析 (2013)
  • Author(s): 小澤厚志、山田正信 他
  • Organizer: 第19回日本家族性腫瘍学会学術集会
  • Place of Presentation: 別府
• [Presentation] 膵β細胞腫瘍発症への変異JunDの関与:β細胞特異的変異JunDトランスジェニックマウスの解析 (2013)
  • Author(s): 小澤厚志、山田正信 他
  • Organizer: 第87回日本内分泌学会学術総会
  • Place of Presentation: 仙台
• [Presentation] 下垂体におけるMEN1遺伝子Exon1 splicing variantの発現解析 (2013)
  • Author(s): 小澤厚志、山田正信 他
  • Organizer: 第23回日本間脳下垂体腫瘍学会学術総会
  • Place of Presentation: 鹿児島
• [Presentation] 変異JunDによる膵神経内分泌腫瘍発症機構の解明：膵β細胞特異的変異JunDトランスジェニックマウスの作製と解析 (2013)
  • Author(s): 小澤厚志、渡邉琢也、岡村孝志、田口 亮、吉野 聡、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、森 昌朋、山田正信
  • Organizer: 第４０回日本神経内分泌学会学術集会
  • Place of Presentation: 宮崎
• [Presentation] MEN1遺伝子Exon1 splicing variantの腫瘍組織における発現解析 (2013)
  • Author(s): 小澤厚志、田口 亮、登丸琢也、石井角保、渋沢信行、佐藤哲郎、森 昌朋、山田正信
  • Organizer: 第１９回日本家族性腫瘍学会学術集会
  • Place of Presentation: 別府
• [Presentation] 膵島腫瘍発症機構における転写因子JunDの役割：膵β細胞特異的変異JunDトランスジェニックマウスの作製と解析 (2013)
  • Author(s): 小澤厚志、山田正信、田口 亮、渋沢信行、岡村孝志、土岐明子、石田恵美、吉野聡、中島康代、登丸琢也、石井角保、橋本貢士、佐藤哲郎、森 昌朋
  • Organizer: 第５６回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本
• [Presentation] 膵β細胞腫瘍発症への変異JunDの関与：β細胞特異的変異JunDトランスジェニックマウスの解析 (2013)
  • Author(s): 小澤厚志、山田正信、田口 亮、Jennifer Garay Guerrero、渋沢信行、登丸琢也、石井角保、橋本貢士、佐藤哲郎、森 昌朋
  • Organizer: 第８７回日本内分泌学会学術総会抄録集
  • Place of Presentation: 仙台
• [Presentation] 膵島腫瘍発症機構における転写因子JunDの役割 (2013)
  • Author(s): 小澤厚志、山田正信、田口亮、渋沢信行、登丸琢也、石井角保、橋本貢士、佐藤哲郎、森昌朋
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本
• [Presentation] 膵β細胞腫瘍発症への変異JunDの関与 (2013)
  • Author(s): 小澤厚志、山田正信、田口亮、Jennifer Garay Guerrero, 渋沢信行、登丸琢也、石井角保、橋本貢士、佐藤哲郎、森昌朋
  • Organizer: 第86回日本内分泌学会学術集会
  • Place of Presentation: 仙台
• [Presentation] 下垂体におけるMEN1遺伝子Exon1 splicing variantの発現解析 (2013)
  • Author(s): 小澤厚志、山田正信、田口亮、渋沢信行、登丸琢也、石井角保、橋本貢士、佐藤哲郎、森昌朋
  • Organizer: 第23回日本間脳下垂体腫瘍学会
  • Place of Presentation: 鹿児島
• [Presentation] 多発性内分泌腫瘍症1型(MEN1)モデルマウスの解析:臓器特異的腫瘍発症機構の解明 (2012)
  • Author(s): 小澤厚志、山田正信 他
  • Organizer: 第86回日本内分泌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] MEN1遺伝子Exon1 splicing variantの組織間における発現解析 (2012)
  • Author(s): 小澤厚志、山田正信、田口亮、渋沢信行、登丸琢也、石井角保、橋本貢士、佐藤哲郎、森昌朋
  • Organizer: 第39回日本神経内分泌学会学術集会
  • Place of Presentation: 北九州
• [Presentation] 多発性内分泌腫瘍症1型(MEN1)モデルマウスの解析 臓器特異的腫瘍発症機構の解明 (2012)
  • Author(s): 小澤厚志、山田正信、田口亮、渋沢信行、登丸琢也、橋本貢士、佐藤哲郎、森昌朋
  • Organizer: 第85回日本内分泌学会学術集会
  • Place of Presentation: 名古屋
• [Presentation] 多発性内分泌腫瘍症１型の組織特異的腫瘍発生分子メカニズムの解明ーモデルマウスの解析 (2011)
  • Author(s): 小澤厚志、Jennifer Garay Guerrero、田口 亮、山田正信、森 昌朋
  • Organizer: 第84回日本内分泌学会学術総会
  • Place of Presentation: 神戸国際展示場（神戸）
• [Presentation] 変異JunDによる膵内分泌腫瘍発症機構：マウスモデルの解析 (2011)
  • Author(s): 小澤厚志、山田正信、田口 亮、登丸琢也、渋沢信行、橋本貢士、佐藤哲郎、森 昌朋
  • Organizer: 第38回日本神経内分泌学会学術集会
  • Place of Presentation: 都道府県会館（東京）
• [Book] 臨床検査ガイド2013〜2014 (2013)
  • Author(s): 小澤厚志他
  • Publisher: 文光堂
• [Book] ホルモンと臨床【内分泌腫瘍発症機構に迫る】 (2013)
  • Author(s): 小澤厚志、山田正信
  • Total Pages: 89
  • Publisher: 医学の世界社
• [Book] ホルモンと臨床【膵内分泌腫瘍】 (2013)
  • Author(s): 小澤厚志、山田正信
  • Total Pages: 72
  • Publisher: 医学の世界社
• [Book] 臨床検査ガイド2013～2014 (2013)
  • Author(s): 小澤厚志、森 昌朋
  • Total Pages: 1107
  • Publisher: 文光堂
• [Book] ホルモンと臨床「内分泌腫瘍発症機構に迫る」 (2012)
  • Author(s): 小澤厚志他
  • Publisher: 医学の世界社
• [Book] ホルモンと臨床「膵内分泌腫瘍」 (2012)
  • Author(s): 水出雅文、小澤厚志他
  • Publisher: 医学の世界社
• [Book] ホルモンと臨床「膵内分泌腫瘍」 (2012)
  • Author(s): 小澤厚志他
  • Publisher: 医学の世界社