Skp2 directs Myc-mediated suppression of p27Kip1 yet has modest effects on Myc-driven lymphomagenesis.
Skp2 directs Myc-mediated suppression of p27Kip1 yet has modest effects on Myc-driven lymphomagenesis.
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DOI：
10.1158/1541-7786.mcr-09-0232
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发表时间：
2010-03
期刊：
影响因子：
--
通讯作者：
Keller UB
中科院分区：
文献类型：
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作者：
Old JB;Kratzat S;Hoellein A;Graf S;Nilsson JA;Nilsson L;Nakayama KI;Peschel C;Cleveland JL;Keller UB
通用的细胞周期蛋白-Cdk抑制剂p27 Kip 1作为一种肿瘤抑制剂发挥作用，p27 Kip 1水平降低意味着在几种人类恶性肿瘤中预后不良。p27 Kip 1水平主要由泛素介导的蛋白质周转调节，其被标记为在其被细胞周期蛋白E-Cdk 2复合物磷酸化后被E3泛素连接酶SCFSkp 2复合物破坏。磷酸化p27 Kip 1的结合由Skp 2 F-box蛋白指导，并且这被其变构调节剂Cks 1大大增强。我们已经证实，在Eμ-Myc转基因小鼠的B细胞中，c-Myc的程序性表达通过诱导Cks 1触发p27 Kip 1的破坏，这种反应控制Myc驱动的增殖，Cks 1的缺失显著延迟Myc诱导的淋巴瘤发生并消除这些肿瘤的扩散。在这里，我们报告Skp 2水平升高是Eμ-Myc淋巴瘤和携带MYC/免疫球蛋白染色体易位的人Burkitt淋巴瘤的特征。正如预期的那样，Myc介导的p27 Kip 1抑制在Skp 2-null Eμ-Myc B细胞中被消除。然而，与Cks 1缺失的影响相比，Skp 2缺失对Myc驱动的增殖和淋巴瘤发生的影响令人惊讶地温和。总的来说，这些发现表明，除了p27 Kip 1之外，Cks 1靶点对Myc驱动的增殖和肿瘤发生至关重要。
The universal cyclin-Cdk inhibitor p27Kip1 functions as a tumor suppressor and reduced levels of p27Kip1 connote poor prognosis in several human malignancies. p27Kip1 levels are predominately regulated by ubiquitin-mediated turnover of the protein, which is marked for destruction by the E3 ubiquitin ligase SCFSkp2 complex following its phosphorylation by the cyclin E-Cdk2 complex. Binding of phospho-p27Kip1 is directed by the Skp2 F-box protein, and this is greatly augmented by its allosteric regulator Cks1. We have established that programmed expression of c-Myc in the B cells of Eμ-Myc transgenic mice triggers p27Kip1 destruction by inducing Cks1, that this response controls Myc-driven proliferation, and that loss of Cks1 markedly delays Myc-induced lymphomagenesis and cancels the dissemination of these tumors. Here, we report that elevated levels of Skp2 are a characteristic of Eμ-Myc lymphomas and of human Burkitt lymphoma that bear MYC/immunoglobulin chromosomal translocations. As expected, Myc-mediated suppression of p27Kip1 was abolished in Skp2-null Eμ-Myc B cells. However, the impact of Skp2 loss on Myc-driven proliferation and lymphomagenesis was surprisingly modest compared to the effects of Cks1 loss. Collectively these findings suggest that Cks1 targets in addition to p27Kip1 are critical for Myc-driven proliferation and tumorigenesis.