Roles of tyrosine phosphorylation of KAP1 in leukemogenesis

• Project/Area Number: 15K19545
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Kumamoto University
• Principal Investigator: Kubota Sho 熊本大学, 国際先端医学研究機構, 特別研究員(PD・RPD) (70747831)
• Research Collaborator: Sashida Goro 熊本大学, 国際先端医学研究機構, 特別招聘教授 (70349447)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: BCR-ABL / CML / KAP1 / TIF1beta / エピジェネティクス / TIF1 / 造血器腫瘍 / 血液学 / 白血病 / 造血幹細胞 / チロシンリン酸化

Outline of Final Research Achievements

BCR-ABL, which is a highly activated oncogenic fusion tyrosine kinase in chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphocytic leukemia (Ph+ ALL). Although it is well known that tyrosine phosphorylation is important for signal transduction in cytoplasm, roles of nuclear tyrosine phosphorylation in nuclear events is poorly understood. We generated a new BCR-ABL knock-in mice model, and we mated mice with conditional KAP1 knockout mice. Using these mice model, we analyzed the function of tyrosine phosphorylation of KAP1 in normal hematopoiesis and leukemogenesis. Analysis for moceluclar mechanism of tyrosine phosphorylation of KAP1 was performed in K562 CML cell line.

Research Products

• [Journal Article] Src acts as an effector for Ku70-dependent suppression of apoptosis through phosphorylation of Ku70 at Tyr-530 (2017)
  • Author(s): Morii, M., Kubota, S., Honda, T., Yuki, R., Morinaga, T., Kuga, T., Tomonaga, T., Yamaguchi, N.-t., and Yamaguchi, N.
  • Journal Title: Journal of Biological Chemistry Volume: 292 Issue: 5 Pages: 1648-1665
  • DOI: 10.1074/jbc.m116.753202
  • Peer Reviewed
• [Journal Article] Role for Tyrosine Phosphorylation of A-kinase Anchoring Protein 8 (AKAP8) in its Dissociation from Chromatin and the Nuclear Matrix (2015)
  • Author(s): Kubota S, Morii M, Yuki R, Yamaguchi N, Yamaguchi H, Aoyama K, Kuga T, Tomonaga T, Yamaguchi N.
  • Journal Title: J Biol Chem Volume: 290 Issue: 17 Pages: 10891-904
  • DOI: 10.1074/jbc.m115.643882
  • Peer Reviewed / Open Access
• [Journal Article] c-Abl-mediated tyrosine phosphorylation of JunB is required for Adriamycin-induced expression of p21. (2015)
  • Author(s): Noritaka Yamaguchi, Ryuzaburo Yuki, Sho Kubota, Kazumasa Aoyama, Takahisa Kuga, Yuuki Hashimoto, Takeshi Tomonaga, and Naoto Yamaguchi.
  • Journal Title: Biochemical Journal Volume: 471 Issue: 1 Pages: 67-77
  • DOI: 10.1042/bj20150372
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] がん遺伝子v-Srcによる細胞周期進行抑制の分子機構 (2017)
  • Author(s): 本田 拓也、鈴木 亘、森井 真理子、添田 修平、阿部 紘平、山口 千尋、久保田 翔、青山 和正、中山 祐治、山口 憲孝、山口 直人
  • Organizer: 日本薬学会第１３７年会
  • Place of Presentation: 仙台
  • Year and Date: 2017-03-24
• [Presentation] RUNX2 super enhancer promotes the development of blastic plasmacytoid dendritic cell neoplasm (2017)
  • Author(s): Sho Kubota, Kenji Tokunaga, Motohiko Oshima, Tomohiro Umezu, Akinori Kanai, Kar Ton Tan, Henry Yang, Eisaku Iwanaga, Norio Asou, Takahiro Maeda, Atsushi Iwama, Kazuma Ohyashiki, Motomi Osato, and Goro Sashida
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] UV照射によるアポトーシス誘導におけるSrcシグナリングの役割. (2015)
  • Author(s): 森井真理子, 久保田 翔, 本田拓也, 青山和正, 幸 龍三郎, 米谷詩織, 山口憲孝, 山口直人.
  • Organizer: BMB2015
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-01
• [Presentation] Src型チロシンキナーゼによるBaxを介したアポトーシス誘導の制御. (2015)
  • Author(s): 森井真理子, 久保田 翔, 本田拓也, 青山和正, 幸 龍三郎, 米谷詩織, 山口憲孝, 山口直人.
  • Organizer: 第14回次世代を担う若手ファーマ・バイオフォーラム2015
  • Place of Presentation: 千葉大学
  • Year and Date: 2015-09-12