Department of Systems BioMedicine, National Research Institute for Child Health and Development, Tokyo, Japan.
PLoS Genet. 2013;9(1):e1003132. doi: 10.1371/journal.pgen.1003132. Epub 2013 Jan 10.
Mastermind-like 1 (MAML1) is a transcriptional co-activator in the Notch signaling pathway. Recently, however, several reports revealed novel and unique roles for MAML1 that are independent of the Notch signaling pathway. We found that MAML1 enhances the transcriptional activity of runt-related transcription factor 2 (Runx2), a transcription factor essential for osteoblastic differentiation and chondrocyte proliferation and maturation. MAML1 significantly enhanced the Runx2-mediated transcription of the p6OSE2-Luc reporter, in which luciferase expression was controlled by six copies of the osteoblast specific element 2 (OSE2) from the Runx2-regulated osteocalcin gene promoter. Interestingly, a deletion mutant of MAML1 lacking the N-terminal Notch-binding domain also enhanced Runx2-mediated transcription. Moreover, inhibition of Notch signaling did not affect the action of MAML1 on Runx2, suggesting that the activation of Runx2 by MAML1 may be caused in a Notch-independent manner. Overexpression of MAML1 transiently enhanced the Runx2-mediated expression of alkaline phosphatase, an early marker of osteoblast differentiation, in the murine pluripotent mesenchymal cell line C3H10T1/2. MAML1(-/-) embryos at embryonic day 16.5 (E16.5) had shorter bone lengths than wild-type embryos. The area of primary spongiosa of the femoral diaphysis was narrowed. At E14.5, extended zone of collagen type II alpha 1 (Col2a1) and Sox9 expression, markers of chondrocyte differentiation, and decreased zone of collagen type X alpha 1 (Col10a1) expression, a marker of hypertrophic chondrocyte, were observed. These observations suggest that chondrocyte maturation was impaired in MAML1(-/-) mice. MAML1 enhances the transcriptional activity of Runx2 and plays a role in bone development.
类脑 MAML1 蛋白（MAML1）是 Notch 信号通路中的转录共激活因子。然而，最近有几项报告揭示了 MAML1 的一些新的、独特的作用，这些作用与 Notch 信号通路无关。我们发现，MAML1 增强了 runt 相关转录因子 2（Runx2）的转录活性，Runx2 是成骨细胞分化和软骨细胞增殖和成熟所必需的转录因子。MAML1 显著增强了 Runx2 介导的 p6OSE2-Luc 报告基因的转录，其中荧光素酶的表达受 Runx2 调控的骨钙素基因启动子中 6 个拷贝的成骨细胞特异性元件 2（OSE2）的控制。有趣的是，缺失了 N 端 Notch 结合结构域的 MAML1 缺失突变体也增强了 Runx2 介导的转录。此外，Notch 信号通路的抑制并不影响 MAML1 对 Runx2 的作用，这表明 MAML1 对 Runx2 的激活可能是 Notch 非依赖性的。MAML1 的过表达瞬时增强了鼠多能间充质细胞系 C3H10T1/2 中转录因子 Runx2 介导的碱性磷酸酶的表达，碱性磷酸酶是成骨细胞分化的早期标志物。在胚胎第 16.5 天（E16.5），MAML1（-/-）胚胎的骨长度比野生型胚胎短。股骨骨干初级松质骨的面积变窄。在 E14.5 时，观察到延伸的 II 型胶原α 1（Col2a1）和 Sox9 表达区，这是软骨细胞分化的标志物，以及减少的 I 型胶原 Xα 1（Col10a1）表达区，这是肥大软骨细胞的标志物。这些观察结果表明，MAML1（-/-）小鼠的软骨细胞成熟受损。MAML1 增强了转录因子 Runx2 的转录活性，并在骨骼发育中发挥作用。
