Skp2 is required for survival of aberrantly proliferating Rb1-deficient cells and for tumorigenesis in Rb1+/- mice.
Skp2 is required for survival of aberrantly proliferating Rb1-deficient cells and for tumorigenesis in Rb1+/- mice.
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视网膜母细胞瘤基因Rb 1的杂合性在剩余功能等位基因自发丢失后的易感组织中促进肿瘤发生先前研究的pRb靶点灭活部分抑制Rb 1 +/-小鼠的肿瘤发生。在这里，我们报告说，pRb靶Skp 2的失活完全防止Rb 1 +/-小鼠自发性肿瘤发生。当Skp 2失活时，黑素营养细胞中的靶向Rb 1缺失会消融整个垂体中叶。Skp 2失活不抑制Rb 1缺失的黑素营养细胞的异常增殖，但诱导其凋亡性死亡。在p27 T187 A敲入小鼠中消除T187上的p27磷酸化再现了Skp 2敲除的效果，鉴定了通过SCFSkp 2泛素连接酶的p27泛素化作为Skp 2在该设置中的基本致瘤作用的潜在机制。RB 1缺陷型人视网膜母细胞瘤细胞在Skp 2敲低后也发生凋亡; p27的异位表达，特别是p27 T187 A突变体，诱导凋亡。这些结果表明，Skp 2成为一个重要的生存基因时，易感细胞发生Rb 1缺陷。
Heterozygosity of the retinoblastoma gene Rb1 elicits tumorigenesis in susceptible tissues following spontaneous loss of the remaining functional allele. Inactivation of previously studied pRb targets partially inhibited tumorigenesis in Rb1+/- mice. Here, we report that inactivation of pRb target Skp2 completely prevents spontaneous tumorigenesis in Rb1+/- mice. Targeted Rb1 deletion in melanotrophs ablates the entire pituitary intermediate lobe when Skp2 is inactivated. Skp2 inactivation does not inhibit aberrant proliferation of Rb1-deleted melanotrophs, but induces their apoptotic death. Eliminating p27 phosphorylation on T187 in p27T187A knockin mice reproduces the effects of Skp2 knockout, identifying p27 ubiquitination by SCFSkp2 ubiquitin ligase as the underlying mechanism for Skp2’s essential tumorigenic role in this setting. RB1-deficient human retinoblastoma cells also undergo apoptosis after Skp2 knockdown; and ectopic expression of p27, especially the p27T187A mutant, induces apoptosis. These results reveal that Skp2 becomes an essential survival gene when susceptible cells incur Rb1 deficiency.
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DOI：
10.1083/jcb.200703034
发表时间：
2007-08-27
期刊：
The Journal of cell biology
影响因子：
--
作者：
Yung Y;Walker JL;Roberts JM;Assoian RK
通讯作者：
Assoian RK
影响因子：
64.8
作者：
Malek, NP;Sundberg, H;Roberts, JM
通讯作者：
Roberts, JM
影响因子：
5.7
作者：
Ji, Peng;Sun, Daqian;Zhu, Liang
通讯作者：
Zhu, Liang
影响因子：
--
作者：
Srinivas S;Watanabe T;Lin CS;William CM;Tanabe Y;Jessell TM;Costantini F
通讯作者：
Costantini F
影响因子：
16
作者：
Kitagawa, Mayumi;Lee, Sang Hyun;McCormick, Frank
通讯作者：
McCormick, Frank