Cbl-b and c-Cbl negatively regulate osteoblast differentiation by enhancing ubiquitination and degradation of Osterix

Choi, You Hee; Han, Younho; Lee, Sung Ho; Jin, Yipeng; Bahn, Minjin; Hur, Kyu Chung; Yeo, Chang Yeol; Lee, Kwang Youl

doi:10.1016/j.bone.2015.02.026

Cited by 26 publications

(22 citation statements)

References 51 publications

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“…3). In our previous report, the E3 ligases, Cbl-b and c-Cbl, induced Osterix ubiquitination and degraded the expression of Osterix 47 . A study conducted by Lian et al .…”

Section: Discussionmentioning

confidence: 76%

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Melatonin promotes osteoblast differentiation by regulating Osterix protein stability and expression

Han

Kim

et al. 2017

Sci Rep

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Although the biological role of melatonin in osteogenic differentiation has been suggested, the mechanism of osteoblast differentiation remains unclear. Thus, the present study investigated the underlying molecular mechanisms based on osteoblast-specific transcription factors. We found that melatonin enhanced BMP-4-induced osteogenic differentiation and increased the expression of osteogenic markers, especially Osterix, which is an essential transcription factor for the differentiation of preosteoblasts into mature osteoblasts in the late stage of osteoblast differentiation. Melatonin treatment increased the expression of Osterix during osteoblast differentiation and stabilized its expression by the inhibition of ubiquitin-proteasome-mediated degradation of Osterix, leading to up-regulated Osterix transcriptional activity on the osteogenic promoter and promoting alkaline phosphatase activity and bone mineralization. Furthermore, treatment with protein kinase A (PKA) inhibitor H89 and protein kinase C (PKC) inhibitor Go6976 blocked the melatonin-induced transcriptional activity and phosphorylation of Osterix, indicating that melatonin regulates Osterix expression via the PKA and PKC signaling pathways. Overall, these findings suggest that melatonin directly regulates the late stage of osteoblast differentiation by enhancing Osterix expression; this provides further evidence of melatonin as a potent agent for treating osteoporosis.

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“…3). In our previous report, the E3 ligases, Cbl-b and c-Cbl, induced Osterix ubiquitination and degraded the expression of Osterix 47 . A study conducted by Lian et al .…”

Section: Discussionmentioning

confidence: 76%

“…Alizarin red S (ARS) staining to evaluate calcium-rich deposits was performed as previously described 47 . Briefly, the cells were fixed in 4% formaldehyde for 15 min, then stained with 0.2% ARS (pH 7.2) solution for 30 min, and then washed twice with phosphate buffered saline (PBS).…”

Section: Methodsmentioning

confidence: 99%

Melatonin promotes osteoblast differentiation by regulating Osterix protein stability and expression

Han

Kim

et al. 2017

Sci Rep

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“…Previous studies indicated that Osx is subjected to proteasome-dependent degradation. [41][42][43] The carboxyl terminus of Hsp70-interacting protein (CHIP), an E3 ligase, is reported to negatively regulate osteoblast differentiation through degradation of several osteogenic transcription factors, including Osx, Runx2, and Smad1/5 42 . Besides, Cbl-b/c-Cbl also promotes Osx degradation.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation‐dependent osterix degradation negatively regulates osteoblast differentiation

et al. 2020

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Proteasome inhibitors exert an anabolic effect on bone formation with elevated levels of osteoblast markers. These findings suggest the important role of the proteasomal degradation of osteogenic regulators, while the underlying molecular mechanisms are not fully understood. Here, we report that the proteasome inhibitors bortezomib and ixazomib markedly increased protein levels of the osteoblastic key transcription factor osterix/Sp7 (Osx). Furthermore, we revealed that Osx was targeted by p38 and Fbw7 for proteasomal degradation. Mechanistically, p38-mediated Osx phosphorylation at S73/77 facilitated Fbw7 interaction to trigger subsequent Osx ubiquitination. Consistent with these findings, p38 knockdown or pharmacological p38 inhibition resulted in Osx protein stabilization. Treatment with p38 inhibitors following osteogenic stimulation efficiently induced osteoblast differentiation through Osx stabilization. Conversely, pretreatment of p38 inhibitor followed by osteogenic challenge impaired osteoblastogenesis via suppressing Osx expression, suggesting that p38 exerts dual but opposite effects in the regulation of Osx level to fine-tune its activity during osteoblast differentiation. Furthermore, Fbw7-depleted human mesenchymal stem cells and primary mouse calvarial cells resulted in increased osteogenic capacity. Together, our findings unveil the molecular mechanisms underlying the Osx protein stability control and suggest that targeting the Osx degradation pathway could help enhance efficient osteogenesis and bone matrix regeneration.

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“…RING finger has intrinsic E3 ligase activity and mediates the transfer of ubiquitin to substrates. Therefore, Cbl-b has dual functions of E3 ubiquitin ligase and adaptor protein [22, 23]. Studies have indicated that Cbl-b promoted the proliferation of breast cancer cells [15].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-891b is an independent prognostic factor of pancreatic cancer by targeting Cbl-b to suppress the growth of pancreatic cancer cells

Dong

Che

et al. 2016

Oncotarget

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Growing evidence has revealed that microRNAs could regulate the proliferation of pancreatic ductal adenocarcinoma (PDAC) cells and predict the prognosis of PDAC. Here the comparative microRNA expression profiles of the good and poor prognosis groups were performed by microRNA microarray. MicroRNA-891b (miR-891b) was screened and validated to be a prognostic predictor of PDAC in the initial group and further evaluated to be an independent predictor for the overall survival of resectable PDACs in an independent cohort. By a series of cellular and animal experiments, as well as clinical specimen analyses, miR-891b was confirmed to target the Cbl-b gene, promot the expression of tumor suppressor p21 protein and inhibit the proliferation of PDAC cells. The results provide a theoretical basis for the study of miR-891b as an independent prognostic predictor of PDAC and the role of miR-891b/Cbl-b pathway in this prediction, as well as the identification of new targets for PDAC.

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Cbl-b and c-Cbl negatively regulate osteoblast differentiation by enhancing ubiquitination and degradation of Osterix

Cited by 26 publications

References 51 publications

Melatonin promotes osteoblast differentiation by regulating Osterix protein stability and expression

Melatonin promotes osteoblast differentiation by regulating Osterix protein stability and expression

Phosphorylation‐dependent osterix degradation negatively regulates osteoblast differentiation

MicroRNA-891b is an independent prognostic factor of pancreatic cancer by targeting Cbl-b to suppress the growth of pancreatic cancer cells

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