Deciphering the mechanisms underlying cancer development induced by deregulation of proteolysis

细胞退出细胞周期的调控在多细胞生物的发育中很重要，也与干细胞的维持有关。此外，细胞周期退出缺陷被认为是癌症的主要原因。然而，负责调节细胞周期退出的机制在很大程度上仍然未知。Fbw7是scf型泛素连接酶复合物的F-box蛋白亚基，它靶向细胞周期的正调节因子，包括c-Myc，使其泛素化并随后被26S蛋白酶体降解，以促进细胞周期退出。与这种功能一致，Fbxw7基因的突变已在各种人类恶性肿瘤中被检测到。我们最近产生了常规和条件Fbxw7基因敲除小鼠，并检查了突变动物的干细胞、祖细胞和分化细胞的细胞周期缺陷。在这里，我们总结了Fbxw7缺陷在包括T细胞、造血干细胞和胚胎成纤维细胞在内的各种细胞类型中的多表型。这些表型揭示了Fbxw7在细胞周期退出、干细胞维持和肿瘤抑制中的生物学作用。

Regulation of the exit of cells from the cell cycle is important in the development of multicellular organisms and is also implicated in the maintenance of stem cells. Furthermore, defects in cell cycle exit are thought to be a major cause of cancer. However, the mechanisms responsible for regulation of cell cycle exit have remained largely unknown. Fbw7 is the F-box protein subunit of an SCF-type ubiquitin ligase complex that targets positive regulators of the cell cycle including c-Myc for ubiquitylation and subsequent degradation by the 26S proteasome in order to promote cell cycle exit. Consistent with such a function, mutations of the Fbxw7 gene have been detected in various human malignancies. We have recently generated conventional and conditional Fbxw7 knockout mice and examined stem cells, progenitor cells, and differentiated cells in the mutant animals for cell cycle defects. Here we summarize the pleiotropic phenotypes of Fbxw7 deficiency in various cell types including T cells, hematopoietic stem cells, and embryonic fibroblasts. Such phenotypes have provided insight into the biological roles of Fbxw7 in cell cycle exit, stem cell maintenance, and oncosuppression.