Myc靶向Cks1以引发对p27Kip1的抑制、细胞增殖和淋巴瘤发生。
Myc targets Cks1 to provoke the suppression of p27Kip1, proliferation and lymphomagenesis.
作者信息
Keller Ulrich B, Old Jennifer B, Dorsey Frank C, Nilsson Jonas A, Nilsson Lisa, MacLean Kirsteen H, Chung Linda, Yang Chunying, Spruck Charles, Boyd Kelli, Reed Steven I, Cleveland John L
机构信息
Department of Biochemistry, St Jude Children's Research Hospital, Memphis, TN, USA.
出版信息
EMBO J. 2007 May 16;26(10):2562-74. doi: 10.1038/sj.emboj.7601691. Epub 2007 Apr 26.
Abstract
Reduced levels of the cyclin-dependent kinase inhibitor p27(Kip1) connote poor prognosis in cancer. In human Burkitt lymphoma and in precancerous B cells and lymphomas arising in Emu-Myc transgenic mice, p27(Kip1) expression is markedly reduced. We show that the transcription of the Cks1 component of the SCF(Skp2) complex that is necessary for p27(Kip1) ubiquitylation and degradation is induced by Myc. Further, Cks1 expression is elevated in precancerous Emu-Myc B cells, and high levels of Cks1 are also a hallmark of Emu-Myc lymphoma and of human Burkitt lymphoma. Finally, loss of Cks1 in Emu-Myc B cells elevates p27(Kip1) levels, reduces proliferation and markedly delays lymphoma development and dissemination of disease. Therefore, Myc suppresses p27(Kip1) expression, accelerates cell proliferation and promotes tumorigenesis at least in part through its ability to selectively induce Cks1.
摘要
细胞周期蛋白依赖性激酶抑制剂p27（Kip1）水平降低预示着癌症预后不良。在人类伯基特淋巴瘤以及Emu-Myc转基因小鼠产生的癌前B细胞和淋巴瘤中，p27（Kip1）的表达显著降低。我们发现，SCF（Skp2）复合物中对p27（Kip1）泛素化和降解所必需的Cks1成分的转录由Myc诱导。此外，Cks1在癌前Emu-Myc B细胞中表达升高，高水平的Cks1也是Emu-Myc淋巴瘤和人类伯基特淋巴瘤的一个标志。最后，Emu-Myc B细胞中Cks1的缺失提高了p27（Kip1）水平，降低了增殖，并显著延迟了淋巴瘤的发展和疾病传播。因此，Myc至少部分通过其选择性诱导Cks1的能力来抑制p27（Kip1）表达、加速细胞增殖并促进肿瘤发生。
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