泛素连接酶E3 Nedd4-like家族与癌症关系的研究进展

Advances in Relationship Between Nedd4-like Family of E3 Ubiquitin Ligases and Cancer

泛素蛋白酶体系统参与体内80%以上蛋白质的降解,调节体内细胞增殖,分化及存活,其功能紊乱可导致包括癌症在内的多种疾病。该系统中泛素连接酶E3 Nedd4-like家族已被证实在多种癌症发生、发展中发挥重要作用。泛素连接酶E3 Nedd4-like家族成员能够调节多种蛋白的泛素化、溶酶体及蛋白酶体降解作用及细胞核转位作用,因而影响着肿瘤发生过程中多条信号转导通路,如TGFβ、EGF、IGF、VEGF、SDF-1及TNFα通路。此外,该家族还可直接调节Smads、p53、KLF、RUNX及Jun等多种癌相关转录因子。由此可见,充分了解E3 Nedd4-like家族对癌症的潜在影响将有利于对生物标志物及药物靶点的认知与开发。现将该家族的主要特点、作用机制及在多种癌症中的表达情况作一综述。

Ubiquitin-proteasome system participates in the degradation of more than 80% of proteins in vivo and is involved in the regulation of cell proliferation, differentiation and survival. Therefore, dysregulations of this system result in pathologies including cancers. Accumulated evidence suggests that E3 ubiquitin ligases, which function actively in ubiquitin-proeasome system, play essential roles in cancer development. Moreover, great progress has been made in the research of Nedd4-like family of E3 ubiquitin ligases related to cancer. Because E3 Nedd4-likes modulate ubiquitination, lysosome or proteasome degradation, and nuclear translocation of diverse proteins, and they regulate important signaling pathways, such as TGFβ, EGF, IGF, VEGF, SDF-1, and TNFα, involved in tumorigenesis. In addition, several E3 Nedd4-likes directly modulate multiple cancer-related transcription factors, such as Smads, p53, KLF, RUNX, Jun, etc. Therefore, better insight of the oncogenic potential of these E3 Nedd4-likes may facilitate the identification and development of biomarkers and drug targets in human cancer. In this review, we provide a comprehensive summary of the characteristics, expression levels and molecular mechanisms of the Nedd4-like family of E3 ubiquitin ligases in human cancer.