Mei Zhichao, Zhang Dawei, Hu Bo, Wang Jing, Shen Xian, Xiao Wuhan
From the Key Laboratory of Aquatic Biodiversity and Conservation and.
the First Hospital of Wenzhou Medical University, Wenzhou 325000, China.
J Biol Chem. 2015 Jun 26;290(26):16202-14. doi: 10.1074/jbc.M115.645978. Epub 2015 May 5.
FBXO32 (MAFbx/Atrogin-1) is an E3 ubiquitin ligase that is markedly up-regulated in muscle atrophy. Although some data indicate that FBXO32 may play an important role in tumorigenesis, the molecular mechanism of FBXO32 in tumorigenesis has been poorly understood. Here, we present evidence that FBXO32 targets the oncogenic protein c-Myc for ubiquitination and degradation through the proteasome pathway. Phosphorylation of c-Myc at Thr-58 and Ser-62 is dispensable for FBXO32 to induce c-Myc degradation. Mutation of the lysine 326 in c-Myc reduces c-Myc ubiquitination and prevents the c-Myc degradation induced by FBXO32. Furthermore, overexpression of FBXO32 suppresses c-Myc activity and inhibits cell growth, but knockdown of FBXO32 enhances c-Myc activity and promotes cell growth. Finally, we show that FBXO32 is a direct downstream target of c-Myc, highlighting a negative feedback regulation loop between c-Myc and FBXO32. Thus, FBXO32 may function by targeting c-Myc. This work explains the function of FBXO32 and highlights its mechanisms in tumorigenesis.
FBXO32（MAFbx/Atrogin-1）是一种E3泛素连接酶，在肌肉萎缩中显著上调。尽管一些数据表明FBXO32可能在肿瘤发生中起重要作用，但其在肿瘤发生中的分子机制仍知之甚少。在此，我们提供证据表明，FBXO32通过蛋白酶体途径靶向致癌蛋白c-Myc进行泛素化和降解。c-Myc在苏氨酸58和丝氨酸62处的磷酸化对于FBXO32诱导c-Myc降解并非必需。c-Myc中赖氨酸326的突变会降低c-Myc的泛素化，并阻止FBXO32诱导的c-Myc降解。此外，FBXO32的过表达会抑制c-Myc活性并抑制细胞生长，但敲低FBXO32会增强c-Myc活性并促进细胞生长。最后，我们表明FBXO32是c-Myc的直接下游靶点，突出了c-Myc与FBXO32之间的负反馈调节环。因此，FBXO32可能通过靶向c-Myc发挥作用。这项工作解释了FBXO32的功能，并突出了其在肿瘤发生中的机制。
