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.

Characterization of the microRNA Transcriptomes and Proteomics of Cochlea Tissue-derived Small Extracellular Vesicles From Different Age of Mice After Birth

“…6c). Most of these proteins are reported to be involved in neurodevelopmental process [77], cilia formation [78], ion homeostasis [79], cell proliferation and differentiation [80], and signaling [81]. These results suggest that the expression patterns of proteins in the cochlear tissue-derived sEVs are correlated with age and may play signi cant roles in the formation of the inner ear system.…”

Targeting the COP9 signalosome for cancer therapy

“…Furthermore, Jab1/CSN5 overexpression tends to correlate with cancer cellular proliferation 70 , vascular invasion 71 , lymph node metastasis 72 and histological differentiation clinical stage 73 . Indeed, Jab1/CSN5 promotes tumorigenesis via degrading several substrates, such as p53 74 , p27 75 , p14ARF 57 , Smad4 76 , and the WNT inhibitor DKK1 77 . These targets of Jab1/CSN5 function as tumor suppressors involved in various cellular processes, such as proliferation, apoptosis, angiogenesis, and the cell cycle 78 .…”

COP9 signalosome complex is a prognostic biomarker and corresponds with immune infiltration in hepatocellular carcinoma

“…In contrast to COPS1 and -2, COPS3 inhibits the growth of lung tumors by blocking cell cycle progression [ 20 ]. Similar to COPS1 and -2, however, COPS5 promotes tumorigenesis via the degradation of several anti-tumorigenic substrates, including p53 [ 21 ], p27 [ 22 ], p14ARF [ 23 ], Smad4 [ 24 ], and the WNT inhibitor DKK177 [ 25 ]. Finally, COPS6 assists in the degradation of tumor suppressor p53 via the stabilization of MDM2 [ 26 , 27 ].…”