Targeted destruction of c-Myc by an engineered ubiquitin ligase suppresses cell transformation and tumor formation
Targeted destruction of c-Myc by an engineered ubiquitin ligase suppresses cell transformation and tumor formation
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DOI：
10.1158/0008-5472.can-05-1581
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发表时间：
2005-09-01
期刊：
影响因子：
11.2
通讯作者：
Nakayama, KL
中科院分区：
文献类型：
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作者：
Hatakeyama, S;Watanabe, M;Nakayama, KL
鉴于c-Myc在许多人类恶性肿瘤中的表达上调，靶向灭活该癌蛋白是一种潜在的治疗癌症的有效策略。泛素-蛋白酶体降解蛋白的途径具有高度的特异性，可以通过工程来消除不需要的蛋白，如癌基因产物。我们现在已经产生了一个融合蛋白(命名为Max-U)，它由May和CRW组成，前者与c-Myc形成异二聚体，后者是U盒型泛素连接酶(E3)。MAX-U在体外能与c-Myc发生物理相互作用，促进c-Myc泛素化。它还降低了c-Myc在体内的稳定性，导致依赖c-Myc的转录活性受到抑制。MAX-U的表达降低了Burkitt淋巴瘤细胞内源性c-Myc的丰度和增殖率。此外，MAX-U的表达而不是其催化失活突变体的表达显著地抑制了过表达c-Myc的NIH3T3细胞的体外锚定非依赖性生长以及这些细胞在裸鼠体内的肿瘤形成。这些发现表明，通过人工E3靶向破坏c-Myc可能是治疗某些人类恶性肿瘤的有效策略。
Given that expression of c-Myc is up-regulated in many human malignancies, targeted inactivation of this oncoprotein is a potentially effective strategy for cancer treatment The ubiquitin-proteasome pathway of protein degradation is highly specific and can be engineered to achieve the elimination of undesirable proteins such as oncogene products. We have now generated a ftision protein (designated Max-U) that is composed both of May, which forms a heterodimer with c-Myc, and of CRW, which is a U box-type ubiquitin ligase (E3). Max-U physically interacted with c-Myc in transfected cells and promoted the ubiquitylation of c-Myc in vitro. It also reduced the stability of c-Myc in vivo, resulting in suppression of transcriptional activity dependent on c-Myc. Expression of Max-U reduced both the abundance of endogenous c-Myc in and the proliferation rate of a Burkitt lymphoma cell line. Furthermore, expression of Max-U but not that of a catalytically inactive mutant thereof markedly inhibited both the anchorage-independent growth in vitro of NIH 3T3 cells that overexpress c-Myc as well as tumor formation by these cells in nude mice. These findings indicate that the targeted destruction of c-Myc by an artificial E3 may represent an effective therapeutic strategy for certain human malignancies.