L-Sox5 and Sox6 Proteins Enhance Chondrogenic miR-140 MicroRNA Expression by Strengthening Dimeric Sox9 Activity*
L-Sox5 and Sox6 Proteins Enhance Chondrogenic miR-140 MicroRNA Expression by Strengthening Dimeric Sox9 Activity*
复制标题
DOI：
10.1074/jbc.m112.343194
复制
发表时间：
2012-04
期刊：
影响因子：
--
通讯作者：
S. Yamashita;S. Miyaki;Y. Kato;Shigetoshi Yokoyama;Tempei Sato;F. Barrionuevo;H. Akiyama;G. Scherer;S. Takada;H. Asahara
中科院分区：
文献类型：
--
作者：
S. Yamashita;S. Miyaki;Y. Kato;Shigetoshi Yokoyama;Tempei Sato;F. Barrionuevo;H. Akiyama;G. Scherer;S. Takada;H. Asahara
背景：miR-140是软骨发育和稳态的关键调节因子。结果：miR-140的近端上游区域具有体内软骨形成启动子活性和L-Sox 5/Sox 6/Sox 9（Sox trio）反应元件。结论：L-Sox 5和Sox 6与Sox 9共同调控miR-140的表达。意义：揭示软骨形成的分子机制对软骨修复和组织功能恢复具有重要意义。Sox 9在早期软骨细胞的启动和促进以及后期成熟的抑制中起关键作用。Sox家族成员L-Sox 5和Sox 6也通过促进Sox 9激活Col 2a 1和Agc 1等软骨细胞特异性基因来发挥软骨发育调节因子的作用;然而，调节机制和其他靶基因在很大程度上尚不清楚。MicroRNA是一类短的非编码RNA，其通过促进靶mRNA降解和/或抑制翻译而充当基因表达的负调节因子。对转基因小鼠的分析表明，miR-140是一种软骨特异性microRNA，可能是软骨发育和体内平衡的关键调节因子。最近的研究结果表明，Sox 9促进miR-140的表达，虽然详细的机制尚未完全了解。在这项研究中，我们证明了pri-miR-140的近端上游区域在体内具有软骨形成启动子活性。在启动子区发现了L-Sox 5/Sox 6/Sox 9（Sox trio）反应元件和详细的结合位点。此外，详细的分析表明，Sox 9作为同源二聚体的DNA结合和/或反式激活能力被L-Sox 5和Sox 6增强。这些发现为Sox三人组的软骨特异性基因调控提供了新的见解。
Background: miR-140 is a critical regulator of cartilage development and homeostasis. Results: The proximal upstream region of miR-140 has in vivo chondrogenic promoter activity and an L-Sox5/Sox6/Sox9 (Sox trio) response element. Conclusion: We reveal that L-Sox5 and Sox6 control miR-140 expression together with Sox9. Significance: Uncovering molecular mechanisms of chondrogenesis has implications for cartilage repair and restoration of tissue function. Sox9 plays a critical role in early chondrocyte initiation and promotion as well as repression of later maturation. Fellow Sox family members L-Sox5 and Sox6 also function as regulators of cartilage development by boosting Sox9 activation of chondrocyte-specific genes such as Col2a1 and Agc1; however, the regulatory mechanism and other target genes are largely unknown. MicroRNAs are a class of short, non-coding RNAs that act as negative regulators of gene expression by promoting target mRNA degradation and/or repressing translation. Analysis of genetically modified mice identified miR-140 as a cartilage-specific microRNA that could be a critical regulator of cartilage development and homeostasis. Recent findings suggest Sox9 promotes miR-140 expression, although the detailed mechanisms are not fully understood. In this study we demonstrate that the proximal upstream region of pri-miR-140 has chondrogenic promoter activity in vivo. We found an L-Sox5/Sox6/Sox9 (Sox trio) response element and detailed binding site in the promoter region. Furthermore, detailed analysis suggests the DNA binding and/or transactivation ability of Sox9 as a homodimer is boosted by L-Sox5 and Sox6. These findings provide new insight into cartilage-specific gene regulation by the Sox trio.