Identification of downstream-initiated c-Myc proteins which are dominant-negative inhibitors of transactivation by full-length c-Myc proteins
Identification of downstream-initiated c-Myc proteins which are dominant-negative inhibitors of transactivation by full-length c-Myc proteins
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DOI：
10.1128/mcb.17.3.1459
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发表时间：
1997-03-01
影响因子：
5.3
通讯作者：
Hann, SR
中科院分区：
文献类型：
--
作者：
Spotts, GD;Patel, SV;Hann, SR
c-myc 基因涉及多种细胞过程，包括增殖、分化和凋亡。除了全长 c-Myc 1 和 2 蛋白外，我们还发现人类、小鼠和鸟类细胞表达由保守下游 AUG 密码子翻译起始产生的较小 c-Myc 蛋白。这些 c-Myc 短 (c-Myc S) 蛋白缺乏大部分 N 端反式激活结构域 但保留了 C 端蛋白二聚化和 DNA 结合结构域。与全长 c-Myc 蛋白一样，c-Myc S 蛋白似乎定位于细胞核，相对不稳定，并且被磷酸化。在几种不同类型细胞的快速生长期，短暂地观察到显着水平的 c-Myc S，通常接近全长 c-Myc 的水平。上游起始密码子的优化导致 c-Myc S 蛋白的合成大大减少，表明“漏扫描”机制导致了这些蛋白的翻译。在一些具有改变的 c-myc 基因的造血肿瘤细胞系中，c-Myc S 蛋白以与全长 c-Myc 相当的水平组成型表达。正如预测的那样，c-Myc S 蛋白不能激活转录并抑制全长 c-Myc 蛋白的反式激活，表明显性失活抑制功能，而这些转录抑制剂会 虽然预计不会像全长 c-Myc 一样发挥作用，但表达高水平 c-Myc S 的肿瘤的出现及其在细胞快速生长过程中的瞬时合成表明这些蛋白质不会干扰全长 c-Myc 的生长促进功能。
The c-myc gene has been implicated in multiple cellular processes including proliferation, differentiation, and apoptosis, In addition to the full-length c-Myc 1 and 2 proteins, we have found that human, murine, and avian cells express smaller c-Myc proteins arising from translational initiation at conserved downstream AUG codons, These c-Myc short (c-Myc S) proteins lack most of the N-terminal transactivation domain but retain the C-terminal protein dimerization and DNA binding domains, As with full-length c-Myc proteins, the c-Myc S proteins appear to be localized to the nucleus, are relatively unstable, and are phosphorylated. Significant levels of c-Myc S, often approaching the levels of full-length c-Myc, are transiently observed during the rapid growth phase of several different types of cells, Optimization of the upstream initiation codons resulted in greatly reduced synthesis of the c-Myc S proteins, suggesting that a ''leaky scanning'' mechanism leads to the translation of these proteins. In some hematopoietic tumor cell lines having altered c-myc genes, the c-Myc S proteins are constitutively expressed at levels equivalent to that of full-length c-Myc, As predicted, the c-Myc S proteins are unable to activate transcription and inhibited transactivation by full-length c-Myc proteins, suggesting a dominant-negative inhibitory function, While these transcriptional inhibitors would not be expected to function as full-length c-Myc, the occurrence of tumors which express constitutive high levels of c-Myc S and their transient synthesis during rapid cell growth suggest that these proteins do not interfere with the growth-promoting functions of full-length c-Myc.