Department of Developmental and Molecular Biology and Medicine, The Albert Einstein Comprehensive Cancer Center and Liver Research Center, Albert Einstein College of Medicine, Bronx, New York, USA.
Nat Genet. 2010 Jan;42(1):83-8. doi: 10.1038/ng.498. Epub 2009 Dec 6.
Heterozygosity of the retinoblastoma gene Rb1 elicits tumorigenesis in susceptible tissues following spontaneous loss of the remaining functional allele. Inactivation of previously studied retinoblastoma protein (pRb) targets partially inhibited tumorigenesis in Rb1(+/-) mice. Here we report that inactivation of pRb target Skp2 (refs. 7,8) 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 knock-in mice reproduces the effects of Skp2 knockout, identifying p27 ubiquitination by SCF(Skp2) 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.
视网膜母细胞瘤基因 Rb1 的杂合性会在剩余功能等位基因自发丢失后引发易感组织的肿瘤发生。先前研究的视网膜母细胞瘤蛋白 (pRb) 靶点的失活部分抑制了 Rb1(+/-) 小鼠的肿瘤发生。在这里，我们报告说，pRb 靶点 Skp2 的失活（参考文献 7,8）完全阻止了 Rb1(+/-) 小鼠的自发性肿瘤发生。当 Skp2 失活时，靶向 Rb1 缺失的黑色素细胞会使整个垂体中间叶消失。Skp2 失活不会抑制 Rb1 缺失的黑色素细胞的异常增殖，但会诱导其凋亡死亡。在 p27T187A 敲入小鼠中消除 p27 在 T187 上的磷酸化可复制 Skp2 敲除的效果，确定由 SCF(Skp2) 泛素连接酶对 p27 的泛素化是 Skp2 在这种情况下发挥其重要致癌作用的潜在机制。Skp2 敲除后，RB1 缺陷型人视网膜母细胞瘤细胞也会发生凋亡；并且 p27 的异位表达，特别是 p27T187A 突变体，会诱导细胞凋亡。这些结果表明，当易感细胞发生 Rb1 缺陷时，Skp2 成为必需的存活基因。
