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

J. Biol. Chem., Vol. 280, Issue 3, 2388-2394, January 21, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/3/2388    most recent M406294200v1 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 Smith, E. Articles by Frenkel, B. Search for Related Content PubMed PubMed Citation Articles by Smith, E. Articles by Frenkel, B. Social Bookmarking                      What's this?

Glucocorticoids Inhibit the Transcriptional Activity of LEF/TCF in Differentiating Osteoblasts in a Glycogen Synthase Kinase-3-dependent and -independent Manner^*

Elisheva Smith and Baruch Frenkel¶

From the Departments of Orthopedic Surgery and Biochemistry and Molecular Biology and Institute for Genetic Medicine, Keck School of Medicine at the University of Southern California, Los Angeles, California 90033

Glucocorticoids, widely used as immune suppressors, cause osteoporosis by inhibiting bone formation. In MC3T3-E1 osteoblast-like cultures, dexamethasone (DEX) activates glycogen synthase kinase-3 (GSK3) and inhibits a differentiation-related cell cycle that occurs at a commitment stage immediately after confluence. Here we show that DEX inhibition of the differentiation-related cell cycle is associated with a decrease in -catenin levels and inhibition of LEF/TCF-mediated transcription. These inhibitory activities are no longer observed in the presence of lithium, a GSK3 inhibitor. DEX decreased the serum-responsive phosphorylation of protein kinase B/Akt-Ser⁴⁷³ within minutes, and this inhibition was also observed after 12 h. When the phosphatidylinositol 3-kinase (PI3K)/Akt pathway was inhibited by wortmannin, DEX no longer inhibited -catenin levels. Furthermore, DEX-mediated inhibition of LEF/TCF transcriptional activity was attenuated in the presence of dominant negative forms of either PI3K or protein kinase B/Akt. These results suggest cross-talk between the PI3K/Akt and Wnt signaling pathways. Consistent with a role for Wnt signaling in the osteoblast differentiation-related cell cycle, wortmannin partially negated the DEX inhibition of this cell cycle. DEX also induced histone deacetylase (HDAC) 1, which is known to inhibit LEF/TCF transcriptional activity. Overexpression of HDAC1 negated the inhibitory effect of DEX on LEF/TCF transcriptional activity. In the presence of trichostatin A, a deacetylase inhibitor, DEX-mediated inhibition of the differentiation-related cell cycle was partially negated. When administered together, wortmannin and trichostatin A completely negated the inhibitory effect of DEX on the differentiation-related cell cycle. These results suggest that inhibition of a PI3K/Akt/GSK3/-catenin/LEF axis and stimulation of HDAC1 cooperate to mediate the inhibitory effect of DEX on Wnt signaling and the osteoblast differentiation-related cell cycle.

Received for publication, June 7, 2004 , and in revised form, September 27, 2004.

^* This work was supported by National Institutes of Health Grants AR049412 and AR47052. 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: Dept. of Biochemistry and Molecular Biology and Institute for Genetic Medicine, Keck School of Medicine at the University of Southern California, 2250 Alcazar St., Los Angeles, CA 90033.

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

This article has been cited by other articles:

				K. Kikuchi, M. Fukuda, T. Ito, M. Inoue, T. Yokoi, S. Chiku, T. Mitsuyama, K. Asai, T. Hirose, and Y. Aizawa Transcripts of unknown function in multiple-signaling pathways involved in human stem cell differentiation Nucleic Acids Res., June 16, 2009; (2009) gkp426v1. [Abstract] [Full Text] [PDF]

				Z. Hamidouche, E. Hay, P. Vaudin, P. Charbord, R. Schule, P. J. Marie, and O. Fromigue FHL2 mediates dexamethasone-induced mesenchymal cell differentiation into osteoblasts by activating Wnt/{beta}-catenin signaling-dependent Runx2 expression FASEB J, November 1, 2008; 22(11): 3813 - 3822. [Abstract] [Full Text] [PDF]

				A. Giustina, G. Mazziotti, and E. Canalis Growth Hormone, Insulin-Like Growth Factors, and the Skeleton Endocr. Rev., August 1, 2008; 29(5): 535 - 559. [Abstract] [Full Text] [PDF]

				F.-S. Wang, J.-Y. Ko, D.-W. Yeh, H.-C. Ke, and H.-L. Wu Modulation of Dickkopf-1 Attenuates Glucocorticoid Induction of Osteoblast Apoptosis, Adipocytic Differentiation, and Bone Mass Loss Endocrinology, April 1, 2008; 149(4): 1793 - 1801. [Abstract] [Full Text] [PDF]

				N. I. zur Nieden, F. D. Price, L. A. Davis, R. E. Everitt, and D. E. Rancourt Gene Profiling on Mixed Embryonic Stem Cell Populations Reveals a Biphasic Role for {beta}-Catenin in Osteogenic Differentiation Mol. Endocrinol., March 1, 2007; 21(3): 674 - 685. [Abstract] [Full Text] [PDF]

				L. Sun, Y. Peng, N. Zaidi, L.-L. Zhu, J. Iqbal, K. Yamoah, X. Wang, P. Liu, E. Abe, B. S. Moonga, et al. Evidence that calcineurin is required for the genesis of bone-resorbing osteoclasts Am J Physiol Renal Physiol, January 1, 2007; 292(1): F285 - F291. [Abstract] [Full Text] [PDF]

				Y. Wang, J. B. Lam, K. S.L. Lam, J. Liu, M. C. Lam, R. L.C. Hoo, D. Wu, G. J.S. Cooper, and A. Xu Adiponectin Modulates the Glycogen Synthase Kinase-3{beta}/{beta}-Catenin Signaling Pathway and Attenuates Mammary Tumorigenesis of MDA-MB-231 Cells in Nude Mice Cancer Res., December 1, 2006; 66(23): 11462 - 11470. [Abstract] [Full Text] [PDF]

				Y. L. Pon and A. S. T. Wong Gonadotropin-Induced Apoptosis in Human Ovarian Surface Epithelial Cells Is Associated with Cyclooxygenase-2 Up-Regulation via the {beta}-Catenin/T-Cell Factor Signaling Pathway Mol. Endocrinol., December 1, 2006; 20(12): 3336 - 3350. [Abstract] [Full Text] [PDF]

				H. W. Lee, J. H. Suh, A Y. Kim, Y. S. Lee, S. Y. Park, and J. B. Kim Histone Deacetylase 1-Mediated Histone Modification Regulates Osteoblast Differentiation Mol. Endocrinol., October 1, 2006; 20(10): 2432 - 2443. [Abstract] [Full Text] [PDF]

				S. Takayama, I. Rogatsky, L. E. Schwarcz, and B. D. Darimont The Glucocorticoid Receptor Represses Cyclin D1 by Targeting the Tcf-beta-Catenin Complex J. Biol. Chem., June 30, 2006; 281(26): 17856 - 17863. [Abstract] [Full Text] [PDF]

				V. Deregowski, E. Gazzerro, L. Priest, S. Rydziel, and E. Canalis Notch 1 Overexpression Inhibits Osteoblastogenesis by Suppressing Wnt/beta-Catenin but Not Bone Morphogenetic Protein Signaling J. Biol. Chem., March 10, 2006; 281(10): 6203 - 6210. [Abstract] [Full Text] [PDF]

				S. M. Ghogomu, S. van Venrooy, M. Ritthaler, D. Wedlich, and D. Gradl HIC-5 Is a Novel Repressor of Lymphoid Enhancer Factor/T-cell Factor-driven Transcription J. Biol. Chem., January 20, 2006; 281(3): 1755 - 1764. [Abstract] [Full Text] [PDF]

				D. J. Mulholland, S. Dedhar, G. A. Coetzee, and C. C. Nelson Interaction of Nuclear Receptors with the Wnt/{beta}-Catenin/Tcf Signaling Axis: Wnt You Like to Know? Endocr. Rev., December 1, 2005; 26(7): 898 - 915. [Abstract] [Full Text] [PDF]