The transcriptional cofactor Jab1/Cops5 is crucial for BMP‐mediated mouse chondrocyte differentiation by repressing p53 activity,Journal of Cellular Physiology

当前位置： X-MOL 学术 › J. Cell. Physiol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

The transcriptional cofactor Jab1/Cops5 is crucial for BMP‐mediated mouse chondrocyte differentiation by repressing p53 activity
Journal of Cellular Physiology ( IF 4.5 ) Pub Date : 2021-01-03 , DOI: 10.1002/jcp.30254
Murali K Mamidi _{1,

2} , William E Samsa _{1,

2} , Lindsay A Bashur ₁ , Yuqing Chen ₃ , Ricky Chan ₄ , Brendan Lee ₃ , Guang Zhou _{1,

2,

5}

Affiliation

We previously reported that the evolutionary conserved transcriptional cofactor Jab1/Cops5 is critical for mouse chondrocyte differentiation by selectively repressing BMP signaling. In this study, we first uncovered that the endogenous Jab1 interacts with endogenous Smad1/5/8. Furthermore, although Jab1 did not directly interact with Acvr1 (Alk2), a key Type I BMP receptor, the interaction between endogenous Smad1/5/8 and Acvr1 was increased in Jab1‐null chondrocytes. Thus, Jab1 might negatively regulate BMP signaling during chondrocyte differentiation in part by sequestering Smad1/5/8 away from Acvr1. Next, to identity Jab1 downstream targets in chondrocytes, we performed RNA‐sequencing analysis of Jab1‐null chondrocytes and discovered a total of 1993 differentially expressed genes. Gene set enrichment analysis revealed that key targets inhibited by Jab1 includes p53, BMP/transforming growth factor beta, and apoptosis pathways. We confirmed that endogenous Jab1 interacts with endogenous p53. There was significantly elevated p53 reporter activity, an enhanced expression of phospho‐p53, and an increased expression of a key p53 downstream target, Puma, in Jab1‐null chondrocytes. Moreover, treatments with a p53‐specific inhibitor and/or a BMP Type I receptor‐specific inhibitor reversed the elevated p53 and BMP signaling activities in Jab1‐null chondrocytes and partially restored columnar growth plate structure in E17.5 Jab1‐null mouse tibia explant cultures. Finally, we demonstrated that the chondrocyte‐specific Jab1 overexpression in mice resulted in smaller‐sized embryos with disorganized growth plates. In conclusion, our data showed that the delicate Jab1‐mediated crosstalk between BMP and p53 pathways is crucial to maintain proper chondrocyte survival and differentiation. Moreover, the appropriate Jab1 expression level is essential for proper skeletal development.

中文翻译：

转录辅助因子 Jab1/Cops5 通过抑制 p53 活性对 BMP 介导的小鼠软骨细胞分化至关重要

我们之前报道过进化保守的转录辅因子 Jab1/Cops5 通过选择性抑制 BMP 信号传导对小鼠软骨细胞分化至关重要。在这项研究中，我们首先发现内源性 Jab1 与内源性 Smad1/5/8 相互作用。此外，尽管 Jab1 不直接与关键的 I 型 BMP 受体 Acvr1 (Alk2) 相互作用，但在 Jab1 缺失的软骨细胞中，内源性 Smad1/5/8 和 Acvr1 之间的相互作用增加了。因此，Jab1 可能通过将 Smad1/5/8 与 Acvr1 隔离开来负调节软骨细胞分化过程中的 BMP 信号传导。接下来，为了识别软骨细胞中的 Jab1 下游靶标，我们对Jab1进行了 RNA 测序分析-无效的软骨细胞，共发现了1993个差异表达基因。基因集富集分析显示，Jab1抑制的关键靶点包括 p53、BMP/转化生长因子 β 和细胞凋亡途径。我们证实内源性 Jab1 与内源性 p53 相互作用。在Jab1缺失的软骨细胞中 p53 报告基因活性显着升高，磷酸化 p53 表达增强，关键 p53 下游靶标 Puma 的表达增加。此外，使用 p53 特异性抑制剂和/或 BMP I 型受体特异性抑制剂治疗可逆转 Jab1 缺失软骨细胞中升高的 p53 和 BMP 信号活性，并部分恢复E17.5 Jab1 中的柱状生长板结构-无效小鼠胫骨外植体培养物。最后，我们证明了小鼠中软骨细胞特异性Jab1的过度表达导致胚胎尺寸更小，生长板杂乱无章。总之，我们的数据表明，BMP 和 p53 通路之间微妙的 Jab1 介导的串扰对于维持适当的软骨细胞存活和分化至关重要。此外，适当的 Jab1 表达水平对于适当的骨骼发育至关重要。

更新日期：2021-01-03

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11