Functional study of leukemia-associated factor AML1

白血病相关因子AML1的功能研究

基本信息

批准号：
17013091
负责人：
KITABAYASHI Issay
金额：
$ 25.6万
依托单位：
National Cancer Center Research Institute and Research Center for Innovative Oncology, National Cancer Center Hospital East
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2009
项目状态：
已结题

项目摘要

The AML1 gene is the most frequent target of chromosome translocations and other mutations in acute myeloid leukemia. We purified AML1 complex and found that the complex contained p300/CBP, MOZ, PML, and HIPK2 as well as CBFb. PML is a nuclear protein that functions as a regulator of transcription, cell proliferation, apoptosis, and myeloid cell differentiation. PML interacts with several transcription factors, such as AML1, PU.1, C/EBP and p53, as well as their co-activators, such as HIPK2 and p300, resulting in the activation of transcription. Although PML is thought to achieve transcription activation by stabilizing the transcription-factor complex, little is known about the underlying molecular mechanism. To clarify the role of PML in transcription regulation, PML complex was purified and Fbx3, Skp1, and Cullin1 were identified as novel components of this complex. Fbx3 formed SCFFbx3 ubiquitin ligase and promoted the degradation of HIPK2 and p300 by the ubiquitin-proteasome pathway. PML inhibited this degradation through a mechanism that unexpectedly did not involve inhibition of the ubiquitination of HIPK2. PML, Fbx3, and HIPK2 synergistically activated p53-induced transcription. Our findings suggest that PML stabilizes the transcription-factor complex by protecting HIPK2 and p300 from SCFFbx3-induced degradation until transcription is completed. In contrast, the leukemia-associated fusion PML-RAR α induced the degradation of HIPK2, suggesting that PML-RAR α degrade co-activators to block transcription by antagonizing PML.

AML1基因是急性髓样白血病中最常见的染色体，例如AML1，PU.1，C/EBP和P53及其共激活因子（例如Hipk2和P300），Allthooth PML虽然是通过转录因子PLEX激活的转录激活，以阐明PML在转录调节中的作用X3，SKP1和CULLIN1被泛素蛋白途径识别为300。相比之下，白血病融合的PML-RARα诱导了Hipk2的降解，这表明PML-RARα降解的共激活因子通过对抗PML来阻止转录。

项目成果

期刊论文数量（68）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mutations and deletions of the CBP gene in human lung cancer.

DOI：
发表时间：
2005-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
M. Kishimoto;T. Kohno;K. Okudela;A. Otsuka;H. Sasaki;C. Tanabe;T. Sakiyama;C. Hirama;I. Kitabayashi;J. Minna;S. Takenoshita;J. Yokota
通讯作者：
M. Kishimoto;T. Kohno;K. Okudela;A. Otsuka;H. Sasaki;C. Tanabe;T. Sakiyama;C. Hirama;I. Kitabayashi;J. Minna;S. Takenoshita;J. Yokota

MOZ is essential for generation of MOZ/MLL-fusion related leukemia

MOZ 对于 MOZ/MLL 融合相关白血病的产生至关重要