Skp1-Cullin-F-box (SCF)-type ubiquitin ligase FBXW7 negatively regulates spermatogonial stem cell self-renewal
Skp1-Cullin-F-box (SCF)-type ubiquitin ligase FBXW7 negatively regulates spermatogonial stem cell self-renewal
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DOI：
10.1073/pnas.1401837111
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发表时间：
2014-06-17
影响因子：
11.1
通讯作者：
Shinohara, Takashi
中科院分区：
文献类型：
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作者：
Kanatsu-Shinohara, Mito;Onoyama, Ichiro;Shinohara, Takashi
精原干细胞（ssc）通过自我更新分裂来支持整个生命中的精子发生。虽然已经发现了几个SSC自我更新的积极调节因子，但对消极调节因子知之甚少。在这里，我们报道了F-box和WD-40结构域蛋白7 (FBXW7)， skp1 - cullin -F-box型泛素连接酶的一个组成部分，是SSC自我更新的负调控因子。FBXW7在未分化精原细胞中以细胞周期依赖的方式表达。尽管人们认为精子发生所必需的肽基脯氨酸顺式/反式异构酶1 （PIN1）会破坏FBXW7，但PIN1的缺失会降低FBXW7的表达。精原细胞移植表明，Fbxw7过表达会降低SSC活性，而Fbxw7缺乏则会增强SSC的定植并导致未分化精原细胞的积累，这表明Fbxw7水平对自我更新和分化至关重要。对FBXW7靶点的筛选显示，FBXW7缺乏上调骨髓细胞瘤癌基因（MYC）和细胞周期蛋白E1 （CCNE1）。虽然Myc/Mycn或Ccne1/Ccne2的缺失会损害SSC的活性，但Myc而非Ccne1的过表达会增加SSC的定植。这些结果表明FBXW7通过MYC的降解负向调节SSC的自我更新。
Spermatogonial stem cells (SSCs) undergo self-renewal divisions to support spermatogenesis throughout life. Although several positive regulators of SSC self-renewal have been discovered, little is known about the negative regulators. Here, we report that F-box and WD-40 domain protein 7 (FBXW7), a component of the Skp1-Cullin-F-box-type ubiquitin ligase, is a negative regulator of SSC self-renewal. FBXW7 is expressed in undifferentiated spermatogonia in a cell cycle-dependent manner. Although peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (PIN1), essential for spermatogenesis, is thought to destroy FBXW7, Pin1 depletion decreased FBXW7 expression. Spermatogonial transplantation showed that Fbxw7 overexpression compromised SSC activity whereas Fbxw7 deficiency enhanced SSC colonization and caused accumulation of undifferentiated spermatogonia, suggesting that the level of FBXW7 is critical for self-renewal and differentiation. Screening of putative FBXW7 targets revealed that Fbxw7 deficiency up-regulated myelo-cytomatosis oncogene (MYC) and cyclin E1 (CCNE1). Although depletion of Myc/Mycn or Ccne1/Ccne2 compromised SSC activity, overexpression of Myc, but not Ccne1, increased colonization of SSCs. These results suggest that FBXW7 regulates SSC self-renewal in a negative manner by degradation of MYC.