A new ubiquitin ligase involved in p57 KIP2 proteolysis regulates osteoblast cell differentiation

• Published in: EMBO reports 2008-09, Vol.9 (9), p.878-884
• Main Authors: Chiba, Tomoki, Kim, Minsoo, Nakamoto, Takashi, Nishimori, Shigeki, Tanaka, Keiji
• Format: Article
• Language: English
• ISSN: 1469-221X; 1469-3178
• DOI: 10.1038/embor.2008.125

Transforming growth factor‐β1 (TGF‐β1) has many physiological functions and inhibits the differentiation of osteoblasts. Previously, we reported that TGF‐β1 stimulation induces the degradation of p57 KIP2 in osteoblasts. p57 KIP2 proteolysis depends on the ubiquitin–proteasome pathway and SMAD‐mediated transcription; however, the molecular mechanism underlying p57 KIP2 degradation has been largely unknown. Here, we show that FBL12, a new F‐box protein expressed in the limb bud of developing embryos, is involved in TGF‐β1‐induced degradation of p57 KIP2 . FBL12 formed an SCF FBL12 complex and directly ubiquitinated p57 KIP2 in a phosphorylation‐dependent manner. Inhibition of FBL12 by RNA interference suppressed the degradation of p57 KIP2 and a dominant‐negative mutant of FBL12 (FBL12ΔF) increased the steady‐state level of p57 KIP2 . Furthermore, wild‐type FBL12 inhibited and FBL12ΔF promoted the differentiation of primary osteoblasts. As overexpression of p57 KIP2 promoted osteoblast differentiation, these results indicate the importance of FBL12 and the degradation of p57 KIP2 in the regulation of osteoblast cell differentiation.