HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 10, 6203-6210, March 10, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/10/6203    most recent M508370200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Deregowski, V. Articles by Canalis, E. Search for Related Content PubMed PubMed Citation Articles by Deregowski, V. Articles by Canalis, E. Social Bookmarking                      What's this?

Notch 1 Overexpression Inhibits Osteoblastogenesis by Suppressing Wnt/-Catenin but Not Bone Morphogenetic Protein Signaling^*

Valerie Deregowski, Elisabetta Gazzerro, Leah Priest, Sheila Rydziel, and Ernesto Canalis¹

From the Department of Research, Saint Francis Hospital and Medical Center, Hartford, Connecticut 06105-1299 and The University of Connecticut School of Medicine, Farmington, Connecticut 06030

Notch proteins are transmembrane receptors that control cell-fate decisions. Upon ligand binding, Notch receptors undergo proteolytic cleavage leading to the release of their intracellular domain (NICD). Overexpression of NICD impairs osteoblastogenesis, but the mechanisms are not understood. We examined consequences of the constitutive activation of Notch 1 in ST-2 cells. Notch opposed the effects of bone morphogenetic protein (BMP)-2 and Wnt 3a on alkaline phosphatase activity (APA). BMP-2 induced the phosphorylation of Smad 1/5/8 and the transactivation of a BMP/Smad-responsive construct (12xSBE-Oc-pGL3), but the effect was not modified by Notch. BMP-2 had minimal effects on the phosphorylation of the mitogen-activated protein kinases ERK, p38, and JNK, in the absence or presence of NICD. Notch overexpression decreased the transactivating effect of Wnt 3a, cytoplasmic -catenin levels, and Wnt-dependent gene expression. Transfection of a mutant -catenin expression construct, or the use of a glycogen synthase kinase 3 inhibitor to stabilize -catenin, partially blocked the inhibitory effect of NICD on Wnt signaling and on APA. HES-1 or Groucho1/TLE1 RNA interference enhanced basal and induced Wnt/-catenin signaling opposing NICD effects, but only HES-1 silencing enhanced Wnt 3a effects on APA. In conclusion, NICD overexpression prevents BMP-2 and Wnt biological effects by suppressing Wnt but not BMP signaling. HES-1 appears to mediate effects of Notch on osteoblastogenesis.

Received for publication, July 29, 2005 , and in revised form, December 26, 2005.

^* This work was supported by grant DK45227 from NIDDK, National Institutes of Health (NIH), by Grant AR21707 from NIAMS/NIH, and by The Belgian American Educational Foundation. 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.

¹ To whom correspondence should be addressed: Dept. of Research, Saint Francis Hospital and Medical Center, 114 Woodland St., Hartford, CT 06105-1299. Tel.: 860-714-4068; Fax: 860-714-8053; E-mail: ecanalis{at}stfranciscare.org.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				H. Fukushima, A. Nakao, F. Okamoto, M. Shin, H. Kajiya, S. Sakano, A. Bigas, E. Jimi, and K. Okabe The Association of Notch2 and NF-{kappa}B Accelerates RANKL-Induced Osteoclastogenesis Mol. Cell. Biol., October 15, 2008; 28(20): 6402 - 6412. [Abstract] [Full Text] [PDF]

				X. Cheng, T. L. Huber, V. C. Chen, P. Gadue, and G. M. Keller Numb mediates the interaction between Wnt and Notch to modulate primitive erythropoietic specification from the hemangioblast Development, October 15, 2008; 135(20): 3447 - 3458. [Abstract] [Full Text] [PDF]

				A. Smerdel-Ramoya, S. Zanotti, V. Deregowski, and E. Canalis Connective Tissue Growth Factor Enhances Osteoblastogenesis in Vitro J. Biol. Chem., August 15, 2008; 283(33): 22690 - 22699. [Abstract] [Full Text] [PDF]

				S. Zanotti, A. Smerdel-Ramoya, L. Stadmeyer, D. Durant, F. Radtke, and E. Canalis Notch Inhibits Osteoblast Differentiation and Causes Osteopenia Endocrinology, August 1, 2008; 149(8): 3890 - 3899. [Abstract] [Full Text] [PDF]

				K. Sakamoto, Y. Tamamura, K.-i. Katsube, and A. Yamaguchi Zfp64 participates in Notch signaling and regulates differentiation in mesenchymal cells J. Cell Sci., May 15, 2008; 121(10): 1613 - 1623. [Abstract] [Full Text] [PDF]

				F. Elefteriou A Notch in Bone, Hey, This Is a Phenotype... IBMS BoneKEy, May 1, 2008; 5(5): 176 - 181. [Full Text] [PDF]

				E. Canalis Notch Signaling in Osteoblasts Sci. Signal., April 29, 2008; 1(17): pe17 - pe17. [Abstract] [Full Text] [PDF]

				S. Bai, R. Kopan, W. Zou, M. J. Hilton, C.-t. Ong, F. Long, F. P. Ross, and S. L. Teitelbaum NOTCH1 Regulates Osteoclastogenesis Directly in Osteoclast Precursors and Indirectly via Osteoblast Lineage Cells J. Biol. Chem., March 7, 2008; 283(10): 6509 - 6518. [Abstract] [Full Text] [PDF]

				P. Hayward, T. Kalmar, and A. Martinez Arias Wnt/Notch signalling and information processing during development Development, February 1, 2008; 135(3): 411 - 424. [Abstract] [Full Text] [PDF]

				E. Gazzerro, A. Smerdel-Ramoya, S. Zanotti, L. Stadmeyer, D. Durant, A. N. Economides, and E. Canalis Conditional Deletion of Gremlin Causes a Transient Increase in Bone Formation and Bone Mass J. Biol. Chem., October 26, 2007; 282(43): 31549 - 31557. [Abstract] [Full Text] [PDF]

				U.-M. Fiuza and A. M. Arias Cell and molecular biology of Notch J. Endocrinol., September 1, 2007; 194(3): 459 - 474. [Abstract] [Full Text] [PDF]

				S. Rydziel, L. Stadmeyer, S. Zanotti, D. Durant, A. Smerdel-Ramoya, and E. Canalis Nephroblastoma Overexpressed (Nov) Inhibits Osteoblastogenesis and Causes Osteopenia J. Biol. Chem., July 6, 2007; 282(27): 19762 - 19772. [Abstract] [Full Text] [PDF]

				C. B. Kessler and A. M. Delany Increased Notch 1 Expression and Attenuated Stimulatory G Protein Coupling to Adenylyl Cyclase in Osteonectin-Null Osteoblasts Endocrinology, April 1, 2007; 148(4): 1666 - 1674. [Abstract] [Full Text] [PDF]

				I. Rubio-Aliaga, D. Soewarto, S. Wagner, M. Klaften, H. Fuchs, S. Kalaydjiev, D. H. Busch, M. Klempt, B. Rathkolb, E. Wolf, et al. A Genetic Screen for Modifiers of the Delta1-Dependent Notch Signaling Function in the Mouse Genetics, March 1, 2007; 175(3): 1451 - 1463. [Abstract] [Full Text] [PDF]

				H. Doi, T. Iso, H. Sato, M. Yamazaki, H. Matsui, T. Tanaka, I. Manabe, M. Arai, R. Nagai, and M. Kurabayashi Jagged1-selective Notch Signaling Induces Smooth Muscle Differentiation via a RBP-J{kappa}-dependent Pathway J. Biol. Chem., September 29, 2006; 281(39): 28555 - 28564. [Abstract] [Full Text] [PDF]