Originally published In Press as doi:10.1074/jbc.M304132200 on May 7, 2003
J. Biol. Chem., Vol. 278, Issue 30, 27939-27944, July 25, 2003
E3 Ubiquitin Ligase Smurf1 Mediates Core-binding Factor 
1/Runx2 Degradation and Plays A Specific Role in Osteoblast Differentiation*
Ming Zhao,
Mei Qiao,
Babatunde O. Oyajobi,
Gregory R. Mundy and
Di Chen 
From the
Department of Cellular and Structural Biology, University of Texas Health
Science Center, San Antonio, Texas 78229-3900
Osteoblast differentiation and bone formation is stimulated by bone
morphogenetic protein (BMP)-2 and its downstream signaling molecules Smad1 and
-5 and the osteoblast-specific transcription factor core-binding factor
1 (Cbfa1). Proteolytic degradation of Smad1 and Cbfa1 is
proteasome-dependent, and intracellular concentrations of Smad1 and Cbfa1 are
enhanced by inhibition of the 26 S proteasome. Smad1 degradation is mediated
by the E3 ubiquitin ligase Smurf1 (Smad ubiquitin regulatory factor 1), but
the specific E3 ligase responsible for Cbfa1 degradation has not been
identified. Because Cbfa1 interacts with Smad1, whose degradation is mediated
by Smurf1, we examined the effect of Smurf1 on Cbfa1 degradation in osteoblast
precursor cells. Smurf1 interacts directly with Cbfa1 and mediates Cbfa1
degradation in a ubiquitin- and proteasome-dependent manner. Because Smurf1
controls the intracellular concentrations of several key molecules in the bone
formation cascade, we examined the effect of a mutant form of Smurf1 in
osteoblasts and found that expression of mutant Smurf1 markedly enhanced
osteoblas tdifferentiation. Smurf1 therefore appears to be an important
regulatory factor in osteoblast differentiation and a potential molecular
target for identification of bone anabolic agents.
Received for publication, April 21, 2003
* This work was supported by NIAMS, National Institutes of Health Grant
AR048920 (to D. C.). The costs of publication of this article were defrayed in
part by the payment of page charges. This article must therefore be hereby
marked "advertisement" in accordance with 18 U.S.C.
Section 1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 210-614-0770 (ext. 239);
Fax: 210-614-0797; E-mail:
chend1{at}uthscsa.edu.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
N. M. Teplyuk, M. Galindo, V. I. Teplyuk, J. Pratap, D. W. Young, D. Lapointe, A. Javed, J. L. Stein, J. B. Lian, G. S. Stein, et al.
Runx2 Regulates G Protein-coupled Signaling Pathways to Control Growth of Osteoblast Progenitors
J. Biol. Chem.,
October 10, 2008;
283(41):
27585 - 27597.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Smerdel-Ramoya, S. Zanotti, L. Stadmeyer, D. Durant, and E. Canalis
Skeletal Overexpression of Connective Tissue Growth Factor Impairs Bone Formation and Causes Osteopenia
Endocrinology,
September 1, 2008;
149(9):
4374 - 4381.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Guo, M. Yamashita, Q. Zhang, Q. Zhou, D. Chen, D. G. Reynolds, H. A. Awad, L. Yanoso, L. Zhao, E. M. Schwarz, et al.
Ubiquitin Ligase Smurf1 Mediates Tumor Necrosis Factor-induced Systemic Bone Loss by Promoting Proteasomal Degradation of Bone Morphogenetic Signaling Proteins
J. Biol. Chem.,
August 22, 2008;
283(34):
23084 - 23092.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. I. Aqeilan, M. Q. Hassan, A. de Bruin, J. P. Hagan, S. Volinia, T. Palumbo, S. Hussain, S.-H. Lee, T. Gaur, G. S. Stein, et al.
The WWOX Tumor Suppressor Is Essential for Postnatal Survival and Normal Bone Metabolism
J. Biol. Chem.,
August 1, 2008;
283(31):
21629 - 21639.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Li, M. Huang, H. Zheng, Y. Wang, F. Ren, Y. Shang, Y. Zhai, D. M. Irwin, Y. Shi, D. Chen, et al.
CHIP promotes Runx2 degradation and negatively regulates osteoblast differentiation
J. Cell Biol.,
June 16, 2008;
181(6):
959 - 972.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Chen, M. Zhu, H. Awad, T.-F. Li, T.-J. Sheu, B. F. Boyce, D. Chen, and R. J. O'Keefe
Inhibition of {beta}-catenin signaling causes defects in postnatal cartilage development
J. Cell Sci.,
May 1, 2008;
121(9):
1455 - 1465.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. P. S. Vohra, M. Fu, and R. O. Heuckeroth
Protein Kinase C{zeta} and Glycogen Synthase Kinase-3{beta} Control Neuronal Polarity in Developing Rodent Enteric Neurons, whereas SMAD Specific E3 Ubiquitin Protein Ligase 1 Promotes Neurite Growth But Does Not Influence Polarity
J. Neurosci.,
August 29, 2007;
27(35):
9458 - 9468.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Giuliani, F. Morandi, S. Tagliaferri, M. Lazzaretti, S. Bonomini, M. Crugnola, C. Mancini, E. Martella, L. Ferrari, A. Tabilio, et al.
The proteasome inhibitor bortezomib affects osteoblast differentiation in vitro and in vivo in multiple myeloma patients
Blood,
July 1, 2007;
110(1):
334 - 338.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Luan, X.-P. Yu, K. Xu, B. Ding, J. Yu, Y. Huang, N. Yang, P. Lengyel, P. E. Di Cesare, and C.-j. Liu
The Retinoblastoma Protein Is an Essential Mediator of Osteogenesis That Links the p204 Protein to the Cbfa1 Transcription Factor Thereby Increasing Its Activity
J. Biol. Chem.,
June 8, 2007;
282(23):
16860 - 16870.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Merciris, C. Marty, C. Collet, M.-C. de Vernejoul, and V. Geoffroy
Overexpression of the Transcriptional Factor Runx2 in Osteoblasts Abolishes the Anabolic Effect of Parathyroid Hormone in Vivo
Am. J. Pathol.,
May 1, 2007;
170(5):
1676 - 1685.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Q. Wang, X. Wei, T. Zhu, M. Zhang, R. Shen, L. Xing, R. J. O'Keefe, and D. Chen
Bone Morphogenetic Protein 2 Activates Smad6 Gene Transcription through Bone-specific Transcription Factor Runx2
J. Biol. Chem.,
April 6, 2007;
282(14):
10742 - 10748.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Giuliani, V. Rizzoli, and G. D. Roodman
Multiple myeloma bone disease: pathophysiology of osteoblast inhibition
Blood,
December 15, 2006;
108(13):
3992 - 3996.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Zhao, M. Qiao, S. E. Harris, D. Chen, B. O. Oyajobi, and G. R. Mundy
The zinc finger transcription factor gli2 mediates bone morphogenetic protein 2 expression in osteoblasts in response to hedgehog signaling.
Mol. Cell. Biol.,
August 1, 2006;
26(16):
6197 - 6208.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Sangadala, S. D. Boden, M. Viggeswarapu, Y. Liu, and L. Titus
LIM Mineralization Protein-1 Potentiates Bone Morphogenetic Protein Responsiveness via a Novel Interaction with Smurf1 Resulting in Decreased Ubiquitination of Smads
J. Biol. Chem.,
June 23, 2006;
281(25):
17212 - 17219.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Shen, X. Wang, H. Drissi, F. Liu, R. J. O'Keefe, and D. Chen
Cyclin D1-Cdk4 Induce Runx2 Ubiquitination and Degradation
J. Biol. Chem.,
June 16, 2006;
281(24):
16347 - 16353.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E.-J. Jeon, K.-Y. Lee, N.-S. Choi, M.-H. Lee, H.-N. Kim, Y.-H. Jin, H.-M. Ryoo, J.-Y. Choi, M. Yoshida, N. Nishino, et al.
Bone Morphogenetic Protein-2 Stimulates Runx2 Acetylation
J. Biol. Chem.,
June 16, 2006;
281(24):
16502 - 16511.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Kaneki, R. Guo, D. Chen, Z. Yao, E. M. Schwarz, Y. E. Zhang, B. F. Boyce, and L. Xing
Tumor Necrosis Factor Promotes Runx2 Degradation through Up-regulation of Smurf1 and Smurf2 in Osteoblasts
J. Biol. Chem.,
February 17, 2006;
281(7):
4326 - 4333.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Shen, M. Chen, Y.-J. Wang, H. Kaneki, L. Xing, R. J. O'Keefe, and D. Chen
Smad6 Interacts with Runx2 and Mediates Smad Ubiquitin Regulatory Factor 1-induced Runx2 Degradation
J. Biol. Chem.,
February 10, 2006;
281(6):
3569 - 3576.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. B. Celil and P. G. Campbell
BMP-2 and Insulin-like Growth Factor-I Mediate Osterix (Osx) Expression in Human Mesenchymal Stem Cells via the MAPK and Protein Kinase D Signaling Pathways
J. Biol. Chem.,
September 9, 2005;
280(36):
31353 - 31359.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. St-Arnaud
Ubiquitin Ligase: What Is Your True Substrate?
IBMS BoneKEy,
July 1, 2005;
2(7):
6 - 10.
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.-j. Liu, E. Chang, J. Yu, C. S. Carlson, L. Prazak, X.-P. Yu, B. Ding, P. Lengyel, and P. E. D. Cesare
The Interferon-inducible p204 Protein Acts as a Transcriptional Coactivator of Cbfa1 and Enhances Osteoblast Differentiation
J. Biol. Chem.,
January 28, 2005;
280(4):
2788 - 2796.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. S. Trausch-Azar, J. Lingbeck, A. Ciechanover, and A. L. Schwartz
Ubiquitin-Proteasome-mediated Degradation of Id1 Is Modulated by MyoD
J. Biol. Chem.,
July 30, 2004;
279(31):
32614 - 32619.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y.-H. Jin, E.-J. Jeon, Q.-L. Li, Y. H. Lee, J.-K. Choi, W.-J. Kim, K.-Y. Lee, and S.-C. Bae
Transforming Growth Factor-{beta} Stimulates p300-dependent RUNX3 Acetylation, Which Inhibits Ubiquitination-mediated Degradation
J. Biol. Chem.,
July 9, 2004;
279(28):
29409 - 29417.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Zhao, M. Qiao, S. E. Harris, B. O. Oyajobi, G. R. Mundy, and D. Chen
Smurf1 Inhibits Osteoblast Differentiation and Bone Formation in Vitro and in Vivo
J. Biol. Chem.,
March 26, 2004;
279(13):
12854 - 12859.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Bellido, A. A. Ali, L. I. Plotkin, Q. Fu, I. Gubrij, P. K. Roberson, R. S. Weinstein, C. A. O'Brien, S. C. Manolagas, and R. L. Jilka
Proteasomal Degradation of Runx2 Shortens Parathyroid Hormone-induced Anti-apoptotic Signaling in Osteoblasts: A PUTATIVE EXPLANATION FOR WHY INTERMITTENT ADMINISTRATION IS NEEDED FOR BONE ANABOLISM
J. Biol. Chem.,
December 12, 2003;
278(50):
50259 - 50272.
[Abstract]
[Full Text]
[PDF]
|
|
|
Copyright © 2003 by the American Society for Biochemistry and Molecular Biology.
