4.7 Article

CDC20 promotes bone formation via APC/C dependent ubiquitination and degradation of p65

期刊

EMBO REPORTS
卷 22, 期 9, 页码 -

出版社

WILEY
DOI: 10.15252/embr.202152576

关键词

APC; C; BMSCs; CDC20; osteogenic differentiation; p65

资金

  1. Beijing Natural Science Foundation [7182183, 7202233]
  2. National Natural Science Foundation of China [87930026, 81970911]

向作者/读者索取更多资源

CDC20, in addition to its well-known role in cell cycle regulation, plays a crucial role in osteogenic commitment of BMSCs. It governs bone formation through regulating ubiquitination and degradation of p65, and knockdown of p65 rescues bone loss in Cdc20 conditional knockout mice.
The E3 ubiquitin ligase complex CDC20-activated anaphase-promoting complex/Cyclosome (APC/C-CDC20) plays a critical role in governing mitotic progression by targeting key cell cycle regulators for degradation. Cell division cycle protein 20 homolog (CDC20), the co-activator of APC/C, is required for full ubiquitin ligase activity. In addition to its well-known cell cycle-related functions, we demonstrate that CDC20 plays an essential role in osteogenic commitment of bone marrow mesenchymal stromal/stem cells (BMSCs). Cdc20 conditional knockout mice exhibit decreased bone formation and impaired bone regeneration after injury. Mechanistically, we discovered a functional interaction between the WD40 domain of CDC20 and the DNA-binding domain of p65. Moreover, CDC20 promotes the ubiquitination and degradation of p65 in an APC11-dependent manner. More importantly, knockdown of p65 rescues the bone loss in Cdc20 conditional knockout mice. Our current work reveals a cell cycle-independent function of CDC20, establishes APC11(CDC20) as a pivotal regulator for bone formation by governing the ubiquitination and degradation of p65, and may pave the way for treatment of bone-related diseases.

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