Small Maf proteins serve as transcriptional cofactors for keratinocyte differentiation in the Keap1-Nrf2 regulatory pathway
Small Maf proteins serve as transcriptional cofactors for keratinocyte differentiation in the Keap1-Nrf2 regulatory pathway
复制标题
DOI：
10.1073/pnas.0305902101
复制
发表时间：
2004-04-27
影响因子：
11.1
通讯作者：
Yamamoto, M
中科院分区：
文献类型：
--
作者：
Motohashi, H;Katsuoka, F;Yamamoto, M
小的Maf蛋白，MafF， MafG和MafK，具有亮氨酸拉链（Zip）结构域，这是与其他bZip转录因子形成同二聚体或异二聚体复合物所必需的。在这项研究中，我们试图确定在体内与Nrf2协同作用以结合Maf识别元件的特定成分的身份。体外研究表明，Nrf2与小Maf蛋白形成异源二聚体，然后与Maf识别元件结合，但在体内支持Nrf2活性的真正伴侣分子尚未明确确定。Nrf2的活性通常受到细胞质抑制因子Keap1的抑制，因此Keap1基因的破坏会导致Nrf2的组成性激活。Nrf2过度活跃导致食管和前胃角化细胞过度增生，导致围产期死亡。然而，同时破坏nrf2使keap1缺失的小鼠免于死亡。我们利用这个系统来研究Nrf2功能是否需要小maf。我们产生了keap1和小maf化合物突变小鼠，并检查这些动物的角化细胞异常是否持续存在。结果表明，在keap1缺失小鼠中，mafG和mafF的缺失逆转了致命的角化细胞功能障碍，使keap1缺失突变小鼠免于围产期死亡。mafG::mafF::keap1三重复合突变小鼠的这种拯救表型与nrf2::keap1复合突变小鼠的表型相同，这表明Maf小蛋白mafG和mafF在体内必须与nrf2在功能上相互配合。
The small Maf proteins, MafF, MafG, and MafK, possess a leucine zipper(Zip) domain that is required for homodimer or heterodimer complex formation with other bZip transcription factors. In this study we sought to determine the identity of the specific constituent that collaboratively interacts with Nrf2 to bind to the Maf recognition element in vivo. Studies in vitro suggested that Nrf2 forms heterodimers with small Maf proteins and then bind to Maf recognition elements, but the bona fide partner molecules supporting Nrf2 activity in vivo have not been definitively identified. Nrf2 activity is usually suppressed by a cytoplasmic repressor, Keap1, so disruption of the keap1 gene causes constitutive activation of Nrf2. Nrf2 hyperactivity results in hyperproliferation of keratinocytes in the esophagus and forestomach leading to perinatal lethality. However, simultaneous disruption of nrf2 rescued keap1-null mice from the lethality. We exploited this system to investigate whether small Mafs are required for Nrf2 function. We generated keap1 and small maf compound mutant mice and examined whether keratinocyte abnormalities persisted in these animals. The data show that loss of mafG and mafF in the keap1-null mice reversed the lethal keratinocyte dysfunction and rescued the keap1-null mutant mice from perinatal lethality. This rescue phenotype of mafG::mafF::keap1 triple compound mutant mice phenocopies that of the nrf2::keap1 compound mutant mice, indicating that the small Maf proteins MafG and MafF must functionally cooperate with Nrf2 in vivo.