runt Homology Domain Transcription Factors (Runx, Cbfa, and AML) Mediate Repression of the Bone Sialoprotein Promoter: Evidence for Promoter Context-Dependent Activity of Cbfa Proteins

doi:10.1128/MCB.21.8.2891-2905.2001

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Molecular and Cellular Biology, April 2001, p. 2891-2905, Vol. 21, No. 8
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.8.2891-2905.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

runt Homology Domain Transcription Factors (Runx, Cbfa, and AML) Mediate Repression of the Bone Sialoprotein Promoter: Evidence for Promoter Context-Dependent Activity of Cbfa Proteins

Amjad Javed,¹ George L. Barnes,² B. O. Jasanya,¹ Janet L. Stein,¹ Louis Gerstenfeld,² Jane B. Lian,¹ and Gary S. Stein¹^,^*

Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts,¹ 01655-0106 and Musculoskeletal Research Laboratories, Department of Orthopaedic Surgery, Boston University Medical Center, Boston, Massachusetts² 02118-2526

Received 16 November 2000/Accepted 22 January 2001

Expression of the bone sialoprotein (BSP) gene, a marker of bone formation, is largely restricted to cells in mineralizedtissues. Recent studies have shown that the Cbfa1 (also knownas Runx2, AML-3, and PEBP2 $alpha$ A) transcription factor supports commitmentand differentiation of progenitor cells to hypertrophic chondrocytesand osteoblasts. This study addresses the functional involvementof Cbfa sites in expression of the Gallus BSP gene. Gel mobilityshift analyses with nuclear extracts from ROS 17/2.8 osteoblasticcells revealed that multiple Cbfa consensus sequences are functionalCbfa DNA binding sites. Responsiveness of the 1.2-kb Gallus BSPpromoter to Cbfa factors Cbfa1, Cbfa2, and Cbfa3 was assayed inosseous and nonosseous cells. Each of the Cbfa factors mediatedrepression of the wild-type BSP promoter, in contrast to theirwell known activation of various hematopoietic and skeletal phenotypicgenes. Suppression of BSP by Cbfa factors was not observed inBSP promoters in which Cbfa sites were deleted or mutated. Expressionof the endogenous BSP gene in Gallus osteoblasts was similarlydownregulated by forced expression of Cbfa factors. Our data indicatethat Cbfa repression of the BSP promoter does not involve thetransducin-like enhancer (TLE) proteins. Neither coexpressionof TLE1 or TLE2 nor the absence of the TLE interaction motif ofCbfa1 (amino acids 501 to 513) influenced repressor activity.However, removal of the C terminus of Cbfa1 (amino acids 362 to513) relieved suppression of the BSP promoter. Our results, togetherwith the evolutionary conservation of the seven Cbfa sites inthe Gallus and human BSP promoters, suggest that suppressor activityby Cbfa is of significant physiologic consequence and may contributeto spatiotemporal expression of BSP during bonedevelopment.

^* Corresponding author. Mailing address: Department of Cell Biology, University of Massachusetts Medical School, 55 Lake Ave.North, Worcester, MA 01655-0106. Phone: (508) 856-5625. Fax: (508)856-6800. E-mail: Gary.Stein{at}umassmed.edu.

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