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The transcriptional cofactor Jab1/Cops5 is crucial for BMP‐mediated mouse chondrocyte differentiation by repressing p53 activity
Author(s) -
Mamidi Murali K.,
Samsa William E.,
Bashur Lindsay A.,
Chen Yuqing,
Chan Ricky,
Lee Brendan,
Zhou Guang
Publication year - 2021
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.30254
Subject(s) - chondrocyte , endogeny , microbiology and biotechnology , cop9 signalosome , puma , chemistry , bone morphogenetic protein , biology , gene , cartilage , biochemistry , anatomy , enzyme , protease , peptide hydrolases
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.