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A new ubiquitin ligase involved in p57KIP2 proteolysis regulates osteoblast cell differentiation

Minsoo Kim, Takashi Nakamoto, Shigeki Nishimori, Keiji Tanaka, Tomoki Chiba

Author Affiliations

  1. Minsoo Kim1,
  2. Takashi Nakamoto1,
  3. Shigeki Nishimori1,
  4. Keiji Tanaka1 and
  5. Tomoki Chiba*,1,2
  1. 1 Laboratory of Frontier Science, Core Technology and Research Center, Tokyo Metropolitan Institute of Medical Science, 3‐18‐22 Honkomagome, Bunkyo‐ku, Tokyo, 113‐8613, Japan
  2. 2 Department of Molecular Biology, Graduate School of Life and Environmental Sciences, University of Tsukuba, 1‐1‐1 Tennodai, Tsukuba City, Ibaraki, 305‐8572, Japan
  1. *Corresponding author. Tel: +81 29 853 4662; Fax: +81 29 853 6887; E‐mail: tchiba{at}biol.tsukuba.ac.jp
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Abstract

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 p57KIP2 in osteoblasts. p57KIP2 proteolysis depends on the ubiquitin–proteasome pathway and SMAD‐mediated transcription; however, the molecular mechanism underlying p57KIP2 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 p57KIP2. FBL12 formed an SCFFBL12 complex and directly ubiquitinated p57KIP2 in a phosphorylation‐dependent manner. Inhibition of FBL12 by RNA interference suppressed the degradation of p57KIP2 and a dominant‐negative mutant of FBL12 (FBL12ΔF) increased the steady‐state level of p57KIP2. Furthermore, wild‐type FBL12 inhibited and FBL12ΔF promoted the differentiation of primary osteoblasts. As overexpression of p57KIP2 promoted osteoblast differentiation, these results indicate the importance of FBL12 and the degradation of p57KIP2 in the regulation of osteoblast cell differentiation.

  • Received December 7, 2007.
  • Revision received May 14, 2008.
  • Accepted June 3, 2008.
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