Bone Morphogenetic Protein 2 Activates Smad6 Gene Transcription through Bone-specific Transcription Factor Runx2

Wang, Qing; Wei, Xiaochao; Zhu, Tianhui; Zhang, Ming; Shen, Run; Xing, Lianping; O’Keefe, Regis J.; Chen, Di

doi:10.1074/jbc.m610997200

Cited by 57 publications

(53 citation statements)

References 31 publications

(33 reference statements)

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“…Overexpression of BMP also increased ALP expression. Despite previous reports that BMPs can regulate Runx2 expression, we did not observe changes in Runx2 expression in DZC regardless of BMP or Noggin overexpression (Jeon et al, 2006;Wang et al, 2007). However, our data do not rule out the possibility that even without gene upregulation, that Runx2 activity might have been increased by increased BMP activity.…”

Section: Bmps and Articular Chondrocyte Hypertrophycontrasting

confidence: 99%

Differences in matrix accumulation and hypertrophy in superficial and deep zone chondrocytes are controlled by bone morphogenetic protein

et al. 2007

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Despite the knowledge that superficial zone chondrocytes (SZC, located within 100 μm of the articular surface) and deep zone chondrocytes (DZC, located near the calcified zone) have distinct phenotypes, previous studies on bone morphogenetic proteins (BMPs) have not differentiated its effects on SZC versus DZC. Using a pellet culture model we have compared phenotype, morphology and matrix accumulation in SZC and DZC with or without adenovirus-mediated overexpression of BMP-2 or -7 or the BMP antagonist Noggin. Greater accumulation of proteoglycan (PG)-rich matrix in the untreated DZC was associated with a hypertrophic phenotype with large cell diameters and high gene expression levels of runt-related transcription factor-2 (Runx2) as well as higher endogenous BMP activity. Noggin overexpression decreased matrix accumulation and cell diameters in SZC and DZC, confirming a role for endogenous BMP in both processes. In DZC, overexpression of either BMP2 or -7 increased cell diameter without increasing PG-rich matrix accumulation. In contrast, in SZC, BMP overexpression increased matrix accumulation and type II collagen gene expression without increasing cell diameter. These data indicate that differences in endogenous BMP activity level and responsiveness to BMPs define, in part, the differences between the SZC and DZC phenotype. They also suggest that SZC may be a more appropriate target for BMP therapy than DZC.

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Section: Bmps and Articular Chondrocyte Hypertrophycontrasting

confidence: 99%

Differences in matrix accumulation and hypertrophy in superficial and deep zone chondrocytes are controlled by bone morphogenetic protein

et al. 2007

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“…The Smad6 promoter is active in blood progenitors and can be transactivated by Runx1. In addition to the previously characterized atypical RBE (GTGGGT) (38), the Ϫ2006/ϩ45 Smad6 promoter region has a number of conserved Ets, Gata, and E-box binding sites that tend to be collectively enriched in promoters of genes that are expressed in hematopoietic cells ( Fig. 2A).…”

Section: Resultsmentioning

confidence: 99%

“…2A). This fragment is known to be active in C2C12 myofibroblasts, and its response to BMP2 is dependent on the atypical RBE (38). A survey of the Smad6 locus for conserved Runx binding sites using CoMoDis (10) failed to identify a single consensus motif (TGYGGT) within 100 kb of the start or end of the gene.…”

Section: Resultsmentioning

confidence: 99%

“…The activity of Runx2, a key regulator of bone development, is also controlled by Smad6 targeting of Runx2 to the proteasome (33). Interestingly, Runx2 recently has been shown to transcriptionally regulate Smad6 expression by binding an atypical Runx binding element (RBE) in the Smad6 promoter (38). This is suggestive of an integrated Runx27Smad6 regulatory loop.…”

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confidence: 99%

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A Runx1-Smad6 Rheostat Controls Runx1 Activity during Embryonic Hematopoiesis

Knezevic

Bee

Wilson

et al. 2011

Molecular and Cellular Biology

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The oncogenic transcription factor Runx1 is required for the specification of definitive hematopoietic stem cells (HSC) in the developing embryo. The activity of this master regulator is tightly controlled during development. The transcription factors that upregulate the expression of Runx1 also upregulate the expression of Smad6, the inhibitory Smad, which controls Runx1 activity by targeting it to the proteasome. Here we show that Runx1, in conjunction with Fli1, Gata2, and Scl, directly regulates the expression of Smad6 in the aorta-gonad-mesonephros (AGM) region in the developing embryo, where HSCs originate. Runx1 regulates Smad6 activity via a novel upstream enhancer, and Runx1 null embryos show reduced Smad6 transcripts in the yolk-sac and c-Kit-positive fetal liver cells. By directly regulating the expression of Smad6, Runx1 sets up a functional rheostat to control its own activity. The perturbation of this rheostat, using a proteasomal inhibitor, results in an increase in Runx1 and Smad6 levels that can be directly attributed to increased Runx1 binding to tissue-specific regulatory elements of these genes. Taken together, we describe a scenario in which a key hematopoietic transcription factor controls its own expression levels by transcriptionally controlling its controller.Cell fate decisions in the developing embryo are coordinated by complex gene regulatory networks. These networks are composed primarily of transcription factors (TFs) and cis-regulatory modules, which together control the rates of gene expression. As a consequence, transcriptional regulatory networks control cell function and identity by controlling the types and amounts of protein that are produced in a cell (7). Largely through the systematic analysis of transcription networks in bacteria and yeast, it is now known that information flow through complex networks is controlled by deploying a recur-

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“…Loss of runx2 leads to severe abrogation of bone development (reviewed in Karsenty, 2008). Genes such as osteocalcin, osteopontin, col10, and smad6, which are involved in osteoblast formation, are all directly regu-lated by binding of Runx2 together with Smad1 on the promoters of these genes (Zhang et al, 2000;Drissi et al, 2003;Wang et al, 2007). Because both Runx2 and BMP signaling are critical for development of these cell types, these data suggest that Runx2 may widely coordinate the expression of BMP target genes involved in osteoblast differentiation.…”

Section: Transcription Factor Partners For Smads In the Regulation Ofmentioning

confidence: 99%

Finding partners: How BMPs select their targets

Blitz

Cho

2009

Developmental Dynamics

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The bone morphogenetic protein (BMP) signaling pathway is a conserved and evolutionarily ancient regulatory module affecting a large variety of cellular behaviors. The evolutionary flexibility in using BMP responses presumably arose by co-option of a canonical BMP signaling cascade to regulate the transcription of diverse batteries of target genes. This begs the question of how seemingly interchangeable BMP signaling components elicit widely different outputs in different cell types, an important issue in the context of understanding how BMP signaling integrates with gene regulatory networks to control development. Because a molecular understanding of how BMP signaling activates different batteries of target genes is an essential prerequisite to comprehending the roles of BMPs in regulating cellular responses, here we review the current knowledge of how BMP-regulated target genes are selected by the signal transduction machinery. We highlight recent studies suggesting the evolutionary conservation of BMP target gene regulation signaling by Schnurri family zinc finger proteins.

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Bone Morphogenetic Protein 2 Activates Smad6 Gene Transcription through Bone-specific Transcription Factor Runx2

Cited by 57 publications

References 31 publications

Differences in matrix accumulation and hypertrophy in superficial and deep zone chondrocytes are controlled by bone morphogenetic protein

Differences in matrix accumulation and hypertrophy in superficial and deep zone chondrocytes are controlled by bone morphogenetic protein

A Runx1-Smad6 Rheostat Controls Runx1 Activity during Embryonic Hematopoiesis

Finding partners: How BMPs select their targets

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