期刊
BLOOD
卷 124, 期 13, 页码 2081-2090出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2014-06-584524
关键词
-
类别
资金
- Deutsche Forschungsgemeinschaft [SFB824, KE 222/7-1]
- Deutsche Jose Carreras Leukamie Stiftung [R11/18]
- Leukemia Lymphoma Society Scholar Award
- National Institutes of Health, National Cancer Institute [CA100603]
- monies from the State of Florida to Scripps Florida
- Swedish Cancer Society
- BioCARE
- Swedish Research Council
- German Cancer Consortium (DKTK)
Myc oncogenic transcription factors (c-Myc, N-Myc, and L-Myc) coordinate the control of cell growth, division, and metabolism. In cancer, Myc overexpression is often associated with aggressive disease, which is in part due to the destruction of select targets by the ubiquitin-proteasome system (eg, SCFSkp2 -directed destruction of the Cdk inhibitor p27(Kip1)). We reasoned that Myc would also regulate SUMOylation, a related means of posttranslational modification of proteins, and that this circuit would play essential roles in Myc-dependent tumorigenesis. Here, we report marked increases in the expression of genes that encode regulators and components of the SUMOylation machinery in mouse and human Myc-driven lymphomas, resulting in hyper-SUMOylation in these tumors. Further, inhibition of SUMOylation by genetic means disables Myc-induced proliferation, triggering G2/M cell-cycle arrest, polyploidy, and apoptosis. Using genetically defined cell models and conditional expression systems, this response was shown to be Myc specific. Finally, in vivo loss-of-function and pharmacologic studies demonstrated that inhibition of SUMOylation provokes rapid regression of Myc-driven lymphoma. Thus, targeting SUMOylation represents an attractive therapeutic option for lymphomas with MYC involvement.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据