Functional in vivo and in vitro analysis of MORC3, which regulates nuclear domain

MORC3（调节核结构域）的功能体内和体外分析

• 批准号: 18590281
• 负责人: INOUE Norimitsu
• 金额: $ 2.55万
• 依托单位: Research Institute, Osaka Medical Center for Cancer and Cardiovascular Disaeses
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590281/
• 关键词: Leukemia; MORC3; PML nuclear body; Hematopoiesis; Transcriptional regulation; 癌; NORC3; 発現制御

Acute promyelocytic leukemia(APL) is caused by the expression of the PML/RARA fusion gene in hematopoietic cells. PML encodes a protein that is involved in the formation of the nuclear subdomains, PML-nuclear bodies(NBs) and recruits many proteins such as tumor suppressor p53 into PML-NBs to regulate the transcription. The expression of PML/RARA fusion protein disrupts PML-NBs in APL. However, Pml knockout mice do not develop abnormal hematopoiesis or leukemia. We have shown that MORC3 localizes in PML-NBs in a manner dependent on GHL-ATPase at its amino-terminus and regulates the localization and transcriptional activity of p53(Mol. Biol. Cell 18, 1701-1709, 2007) . To analyze functions of MORC3 in vivo, we have generates Morc3 -/- mice. All Morc3 -/- mice died at birth or within a day. Morc3 +/+, +/- and -/- embryos at 18.5 days postcoitum(dpc) were present at almost the expected Mendelian ratio. Morc3 -/- mice presented with hepatomegaly by the infiltration of Gr-1 and Mac-1 double positive myeloid cells around vessels and small thymus at 18.5 dpc embryo. To characterize the abnormal hematopoiesis in Morc3-/-, we transplanted 14.5 dpc Morc3 -/- or +/+ fetal liver cells into lethally irradiated syngeneic mice. About two months after transplantation, the Morc3 -/- fetal liver transplanted mice presented with dermal inflammation and had more Gr-1 and Mac-1 double positive myeloid cells in skin, spleen and liver than the wild type transplanted mice. The differentiation of these myeloid cells into mature macrophage was impaired. The deficiency of MORC3 induced immature myeloid cells characterized by c-Kit expression. We presented these results in 66the annual meeting of the Japanese cancer association and are preparing the paper.

急性早幼粒细胞白血病（APL）是由造血细胞中PML/RARA融合基因的表达引起的。PML编码一种参与核亚结构域（PML-核体（NB））形成的蛋白，并将许多蛋白如肿瘤抑制因子p53募集到PML-NB中以调节转录。PML/RARA融合蛋白的表达破坏了APL中的PML-NB。然而，Pml基因敲除小鼠不发生异常造血或白血病。我们已经证明，MORC 3以依赖于其氨基末端GHL-ATP酶的方式定位在PML-NB中，并调节p53的定位和转录活性（Mol. Biol. Cell 18，1701-1709，2007）。为了分析MORC 3在体内的功能，我们产生了MORC 3-/-小鼠。所有Morc 3-/-小鼠在出生时或在一天内死亡。Morc 3 +/+、+/-和-/-胚胎在交配后18.5天（dpc）几乎以预期的孟德尔比率存在。Morc 3-/-小鼠在18.5 dpc胚胎出现肝肿大，表现为血管周围和小胸腺周围的Gr-1和Mac-1双阳性髓样细胞浸润。为了表征Morc 3-/-中的异常造血，我们将14.5dpc Morc 3-/-或+/+胎肝细胞移植到致死性照射的同基因小鼠中。移植后约2个月，Morc 3-/-胎肝移植小鼠出现皮肤炎症，皮肤、脾脏和肝脏中Gr-1和Mac-1双阳性髓系细胞比野生型移植小鼠多。这些髓样细胞向成熟巨噬细胞的分化受损。MORC 3的缺陷诱导以c-Kit表达为特征的未成熟髓样细胞。我们在日本癌症协会的66届年会上介绍了这些结果，并正在准备论文。

项目成果

Antitumor NK activation induced by the Toll-like receptor 3-TICAM-1 (TRIF) pathway in myeloid dendritic cells

• DOI: 10.1073/pnas.0605978104
• 发表时间: 2007-01-02
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Akazawa, Takashi;Ebihara, Takashi;Seya, Tsukasa
• 通讯作者: Seya, Tsukasa

「研究成果報告書概要(和文)」より

摘自《研究结果报告摘要（日文）》

• 发表时间: 2005
• 作者: Kawauchi;et. al.;Nishimura et al.;Dezawa et al.;Yoshizawa et al.;星野 幹雄;星野 幹雄
• 通讯作者: 星野 幹雄

Dynamic Regulation of P53 PML-nuclear body localization and cellular senescence by MORC3.

MORC3 对 P53 PML-核体定位和细胞衰老的动态调节。

• 发表时间: 2007
• 期刊: Molecular Biology of the cell 18
• 作者: Kubo-Murai;M.;Takahashi K.
• 通讯作者: Takahashi K.

Tumor immunotherapy using bone marrow-derived dendritic cells overexpressing Toll-like receptor adaptors

• DOI: 10.1016/j.febslet.2007.06.019
• 发表时间: 2007-07-24
• 期刊: FEBS LETTERS
• 影响因子: 3.5
• 作者: Akazawa, Takashi;Shingai, Masashi;Seya, Tsukasa
• 通讯作者: Seya, Tsukasa

MORC3とSUMO

MORC3 和相扑

• 发表时间: 2006
• 作者: Takahashi;M.;Yokoe;S.;Asahi;M.;Lee;SH.;Li;W.;Osumi;D.;Miyoshi;E.;Taniguchi;N;井上徳光;Yokoe S.;Li W.;井上 徳光;井上徳光;Park YS.;Norimitsu Inoue;吉田直史;井上徳光
• 通讯作者: 井上徳光