SUMOylation negatively regulates transcriptional and oncogenic activities of MafA
SUMOylation negatively regulates transcriptional and oncogenic activities of MafA
复制标题
DOI：
10.1111/j.1365-2443.2010.01431.x
复制
发表时间：
2010-09-01
期刊：
影响因子：
2.1
通讯作者：
Kataoka, Kohsuke
中科院分区：
文献类型：
--
作者：
Kanai, Kenichi;Reza, Hasan Mahmud;Kataoka, Kohsuke
MAF蛋白(即c-MAF、MafA和MafB)的异常表达导致人类多发性骨髓瘤和鸡胚胎成纤维细胞的致癌转化。MAF蛋白是组织特异性基因表达的转录激活因子，也是细胞分化的调节因子。例如，MafA是鸡晶体蛋白基因和晶状体分化程序的关键调控因子。在哺乳动物中，Mafa对于胰腺中成熟的产生胰岛素的β细胞的发育是必不可少的。研究表明，MafA蛋白的稳定性受多个丝氨酸和苏氨酸残基的磷酸化调控。在这里，我们报告Maf蛋白也被小泛素样修饰物(SUMO)蛋白在氨基末端反式激活器域的保守赖氨酸残基上进行翻译后修饰。突变株MafA(K32R)在αA-晶状体蛋白或胰岛素基因启动子驱动的荧光素酶报告基因反式激活方面比野生型MafA更有效。体外电穿孔试验表明，K32R突变体比野生型MafA能更有效地诱导β-晶体蛋白基因的异位表达。我们还证明了K32R突变体对鸡成纤维细胞系DF-1的诱导集落形成能力增强。因此，SUMO化是MafA的功能性翻译后修饰，负向调节其转录和转化活性。
Dysregulated expression of Maf proteins (namely c-Maf, MafA and MafB) leads to multiple myeloma in humans and oncogenic transformation of chicken embryonic fibroblasts. Maf proteins are transcriptional activators of tissue-specific gene expression and regulators of cell differentiation. For example, MafA is a critical regulator of crystallin genes and the lens differentiation program in chickens. In mammals, MafA is essential for the development of mature insulin-producing beta-cells of pancreas. It has been shown that MafA protein stability is regulated by phosphorylations at multiple serine and threonine residues. Here, we report that Maf proteins are also post-translationally modified by small ubiquitin-like modifier (SUMO) proteins at a conserved lysine residue in the amino-terminal transactivator domain. A SUMOylation-deficient mutant of MafA (K32R) was more potent than wild-type MafA in transactivating luciferase reporter construct driven by alpha A-crystallin or insulin gene promoter. In ovo electroporation into developing chicken embryo showed that the K32R mutant induced ectopic delta-crystallin gene expression more efficiently than the wild-type MafA. We also demonstrated that the K32R mutant had enhanced ability to induce colony formation of a chicken fibroblast cell line DF-1. Therefore, SUMOylation is a functional post-translational modification of MafA that negatively regulates its transcriptional and transforming activities.