RhoB facilitates c-Myc turnover by supporting efficient nuclear accumulation of GSK-3
RhoB facilitates c-Myc turnover by supporting efficient nuclear accumulation of GSK-3
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DOI：
10.1038/sj.onc.1209174
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发表时间：
2006-03-02
期刊：
影响因子：
8
通讯作者：
Prendergast, GC
中科院分区：
文献类型：
--
作者：
Huang, M;Kamasani, U;Prendergast, GC
小的GTdR RhoB部分通过限制细胞增殖来抑制癌症。然而，人们对它用来实现这一目标的机制知之甚少。最近的研究将RhoB与Akt的运输联系起来，Akt通过其对糖原合成酶激酶-3（GSK-3）的调节在控制c-Myc癌蛋白的稳定性方面具有重要作用。c-Myc稳定化可能是人类肿瘤发生的根本特征，因为它表型模仿了SV 40小T抗原在人类细胞转化中的重要贡献。在这项研究中，我们表明，RhoB在建立或转化的小鼠成纤维细胞中指导c-Myc的有效周转，并且在人类癌症中常见的RhoB的衰减是提高c-Myc水平的充分原因。由RhoB缺失引起的c-Myc水平的增加了无效细胞的增殖，而在无效细胞中恢复RhoB降低了c-Myc的稳定性并抑制了细胞增殖。机制分析表明，RhoB促进GSK-3的核积累和GSK-3介导的c-Myc T58磷酸化，这是c-Myc泛素化和降解的关键位点。RhoB缺失限制GSK-3的核定位，减少T58磷酸化，并稳定c-Myc。这些影响与Akt磷酸化或定位的变化无关，然而，在GSK-3调节性Akt相关激酶、血清和糖皮质激素诱导的蛋白激酶（SGK）的磷酸化和定位中观察到差异。RhoB支持GSK-3依赖性c-Myc周转的能力提供了一种机制，RhoB通过该机制限制肿瘤转化细胞的增殖。
The small GTPase RhoB suppresses cancer in part by limiting cell proliferation. However, the mechanisms it uses to achieve this are poorly understood. Recent studies link RhoB to trafficking of Akt, which through its regulation of glycogen synthase kinase-3 (GSK-3) has an important role in controlling the stability of the c-Myc oncoprotein. c-Myc stabilization may be a root feature of human tumorigenesis as it phenocopies an essential contribution of SV40 small T antigen in human cell transformation. In this study we show that RhoB directs efficient turnover of c-Myc in established or transformed mouse fibroblasts and that the attenuation of RhoB which occurs commonly in human cancer is a sufficient cause to elevate c-Myc levels. Increased levels of c-Myc elicited by RhoB deletion increased the proliferation of nullizygous cells, whereas restoring RhoB in null cells decreased the stability of c-Myc and restrained cell proliferation. Mechanistic analyses indicated that RhoB facilitated nuclear accumulation of GSK-3 and GSK-3-mediated phosphorylation of c-Myc T58, the critical site for ubiquitination and degradation of c-Myc. RhoB deletion restricted nuclear localization of GSK-3, reduced T58 phosphorylation, and stabilized c-Myc. These effects were not associated with changes in phosphorylation or localization of Akt, however, differences were observed in phosphorylation and localization of the GSK-3 regulatory Akt-related kinase, serum- and glucocorticoid-inducible protein kinase (SGK). The ability of RhoB to support GSK-3-dependent turnover of c-Myc offers a mechanism by which RhoB acts to limit the proliferation of neoplastically transformed cells.