A conserved Myc protein domain, MBIV, regulates DNA binding, apoptosis, transformation, an G2 arrest
A conserved Myc protein domain, MBIV, regulates DNA binding, apoptosis, transformation, an G2 arrest
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DOI：
10.1128/mcb.01959-05
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发表时间：
2006-06-01
影响因子：
5.3
通讯作者：
Cole, Michael D.
中科院分区：
文献类型：
--
作者：
Cowling, Victoria H.;Chandriani, Sanjay;Cole, Michael D.
在整个进化过程中，MYC的癌基因家族都很好地保守了。在这里，我们介绍了从鱼到人的C-，N-和L-MYC保守的域的表征，N-Myc317-337，指定为MYC Box IV（MBIV）。该结构域的缺失导致MYC诱导的凋亡和某些转化测定法的缺陷，但不能在细胞增殖中。与其他MYC突变体不同，Myc Delta MBIV并不是一个简单的功能丧失突变体，因为它对于G中的G，在原代细胞中停滞过度。对N-MYC Delta MBIV调控的基因的微阵列分析表明，它的反式激活和抑制作用弱，但不如N-MYC Delta MBII那么有缺陷。尽管突变区域不是先前定义的DNA结合结构域的一部分，但我们发现N-MYC Delta MBIV对DNA的亲和力明显低于体外野生型蛋白。此外，染色质免疫沉淀显示N-Myc Delta MBIV与体内某些靶基因的结合减少，这与反式激活中的缺陷有关。因此，该保守的域在MYC DNA结合活性中具有出乎意料的作用。这些数据还提供了与DNA结合活性调节有关的MYC功能的新分离。
The myc family of oncogenes is well conserved throughout evolution. Here we present the characterization of a domain conserved in c-, N-, and L-Myc from fish to humans, N-Myc317-337, designated Myc box IV (MBIV). A deletion of this domain leads to a defect in Myc-induced apoptosis and in some transformation assays but not in cell proliferation. Unlike other Myc mutants, Myc Delta MBIV is not a simple loss-of-function mutant because it is hyperactive for G, arrest in primary cells. Microarray analysis of genes regulated by N-Myc Delta MBIV reveals that it is weakened for transactivation and repression but not nearly as defective as N-Myc Delta MBII. Although the mutated region is not part of the previously defined DNA binding domain, we find that N-Myc Delta MBIV has a significantly lower affinity for DNA than the wild-type protein in vitro. Furthermore, chromatin immunoprecipitation shows reduced binding of N-Myc Delta MBIV to some target genes in vivo, which correlates with the defect in transactivation. Thus, this conserved domain has an unexpected role in Myc DNA binding activity. These data also provide a novel separation of Myc functions linked to the modulation of DNA binding activity.