The transcriptional cofactor Jab1/Cops5 is crucial for BMP-mediated mouse chondrocyte differentiation by repressing p53 activity.

ABSTRACT: 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.

SUBMITTER: Mamidi MK 

PROVIDER: S-EPMC8131218 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature