Dexamethasone Enhancement of Betaglycan (TGF-β Type III Receptor) Gene Expression in Osteoblast-like Cells

Nakayama, Hiroko; Ichikawa, Fumihiko; Andres, Janet L.; Massagué, Joan; Noda, Masaki

doi:10.1006/excr.1994.1091

Cited by 31 publications

(19 citation statements)

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“…Furthermore, the increase in activity mediated by RA was observed independently of the presence of serum. This effect of RA is consistent with a report by Nakayama et al (53), who found that RA increases the levels of betaglycan mRNA in osteoblast-like cells. It is particularly interesting that these growth factors and RA, which are known to be expressed in the vicinity of condensing mesenchymal cells and limb buds during early developmental stages (54 -57), modulate betaglycan expression.…”

Section: Figsupporting

confidence: 93%

Betaglycan Expression Is Transcriptionally Up-regulated during Skeletal Muscle Differentiation

López‐Casillas¹,

Riquelme²,

Pérez-Kato³

et al. 2003

Journal of Biological Chemistry

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Betaglycan is a membrane-anchored proteoglycan coreceptor that binds transforming growth factor ␤ (TGF-␤) via its core protein and basic fibroblast growth factor through its glycosaminoglycan chains. In this study we evaluated the expression of betaglycan during the C 2 C 12 skeletal muscle differentiation. Betaglycan expression, as determined by Northern and Western blot, was up-regulated during the conversion of myoblasts to myotubes. The mouse betaglycan gene promoter was cloned, and its sequence showed putative binding sites for SP1, Smad3, Smad4, muscle regulatory factor elements such as MyoD and MEF2, and retinoic acid receptor. Transcriptional activity of the mouse betaglycan promoter reporter was also up-regulated in differentiating C 2 C 12 cells. We found that MyoD, but not myogenin, stimulated this transcriptional activity even in the presence of high serum. Betaglycan promoter activity was increased by RA and inhibited by the three isoforms of TGF-␤. On the other hand, basic fibroblast growth factor, BMP-2, and hepatocyte growth factor/scatter factor, which are inhibitors of myogenesis, had little effect. In myotubes, up-regulated betaglycan was also detectable by TGF-␤ affinity labeling and immunofluorescence microscopy studies. The latter indicated that betaglycan was localized both on the cell surface and in the ECM. Forced expression of betaglycan in C 2 C 12 myoblasts increases their responsiveness to TGF-␤2, suggesting that it performs a TGF-␤ presentation function in this cell lineage. These results indicate that betaglycan expression is up-regulated during myogenesis and that MyoD and RA modulate its expression by a mechanism that is independent of myogenin.Skeletal muscle myoblasts are the precursors to skeletal muscle fibers. During development these cells are maintained in a proliferative and undifferentiated state until appropriate signals cause them to undergo conversion into multinucleated myotubes.A network of muscle regulatory factors (MRFs), 1 some of which have been identified and characterized, governs this process. When myogenesis begins, myogenic regulatory genes encoding factors of the MyoD family are activated (myogenin, MRF4, and MRF5). These factors bind to specific DNA consensus sites called E boxes, which function as transcriptional enhancers of muscle differentiation genes (for review see Ref.

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Section: Figsupporting

confidence: 93%

Betaglycan Expression Is Transcriptionally Up-regulated during Skeletal Muscle Differentiation

López‐Casillas¹,

Riquelme²,

Pérez-Kato³

et al. 2003

Journal of Biological Chemistry

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“…In osteoblasts, we found that TRIII promoter activity was induced by glucocorticoid and suppressed by BMP-2. Although promoter-dependent reporter gene expression only represents an indication of relative changes in authentic TRIII gene expression, the magnitude of the effects that we observed were consistent with our earlier evidence for changes in TGF-␤ binding to TRIII and on TRIII mRNA (12,13,38,39). Importantly, analogous effects are either not seen or less evident in undifferentiated periosteal cells or fibroblasts (Refs.…”

Section: Table IIsupporting

confidence: 90%

“…In isolated bone cells, TR mRNAs and proteins exhibit relatively short half-lives, offering the opportunity for rapid changes in TGF-␤ sensitivity (40). Moreover, osteotropic factors like BMP-2, glucocorticoid, PTH, and PTH-related protein specifically alter the TR profile and modify the effects of TGF-␤ on osteoblasts (10,12,13,38,39,41). To understand these events at the molecular level, we first isolated and cloned the rat TRI gene promoter and characterized several cis-and trans-acting elements that control constitutive and hormone-dependent TRI expression (24, 25, 39, 42).…”

Section: Discussionmentioning

confidence: 99%

Cloning the Promoter for Transforming Growth Factor-β Type III Receptor

Ji¹,

Chen²,

McCarthy

et al. 1999

Journal of Biological Chemistry

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Transforming growth factor-␤ binds to three high affinity cell surface molecules that directly or indirectly regulate its biological effects. The type III receptor (TRIII) is a proteoglycan that lacks significant intracellular signaling or enzymatic motifs but may facilitate transforming growth factor-␤ binding to other receptors, stabilize multimeric receptor complexes, or segregate growth factor from activating receptors. Because various agents or events that regulate osteoblast function rapidly modulate TRIII expression, we cloned the 5 region of the rat TRIII gene to assess possible control elements. DNA fragments from this region directed high reporter gene expression in osteoblasts. Sequencing showed no consensus TATA or CCAAT boxes, whereas several nuclear factors binding sequences within the 3 region of the promoter co-mapped with multiple transcription initiation sites, DNase I footprints, gel mobility shift analysis, or loss of activity by deletion or mutation. An upstream enhancer was evident 5 proximal to nucleotide ؊979, and a silencer region occurred between nucleotides ؊2014 and ؊2194. Glucocorticoid sensitivity mapped between nucleotides ؊687 and ؊253, whereas bone morphogenetic protein 2 sensitivity comapped within the silencer region. Thus, the TRIII promoter contains cooperative basal elements and dispersed growth factor-and hormone-sensitive regulatory regions that can control TRIII expression by osteoblasts. Several cell surface receptors for transforming growth factor-␤ (TGF-␤)1 are now known. Type I and type II receptors (TRI and TRII) have intracellular kinase domains responsible for heterologous receptor activation or downstream signal transduction (1-4). The type III receptor (TRIII), a membraneanchored proteoglycan also termed betaglycan, is thought to have a biological function distinct from TRI and TRII (5-7). The rat TRIII gene encodes a 91.6-kDa protein core that is modified by approximately 10 kDa of N-linked glycosyl residues and 150 -200 kDa of heparan and chondroitin sulfate side chains.TRIII has a relatively short, 43-amino acid cytoplasmic domain that lacks commonly recognized protein docking or kinase like motifs but is enriched with serines and threonines to approximately 42% (5, 6).TRIII is prevalent on many fetal cells, where it can be the most abundant TGF-␤-binding site. All TGF-␤ isoforms bind to TRIII with comparably high affinity, although this is about 3-5-fold less than that for TRI and TRII (7). Certain cells lack TRIII but maintain TGF-␤ sensitivity. Nonetheless, TRIII may attract and enhance TGF-␤ binding to TRII and form a more stable ligand-receptor complex (6). On certain cell types this appears more pronounced or limited to the TGF-␤2 isoform (8, 9). Moreover, disproportionately high levels of TRIII may sequester and possibly limit its binding to signaling receptor complexes (10 -12).The relative amount of TRIII is thought to vary with development, with differentiation, or in a tissue-specific manner. For example, TRIII levels are prevalent on less different...

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“…At the transcriptional level, TβRIII expression is negatively regulated by TGF-β1 through inhibition of the proximal promoter in multiple cell types, including breast, ovarian, and small cell lung cancer cell lines, as well as by bone morphogenetic protein-2 (BMP-2) in osteoblast cell lines [20, 28-29]. Expression of TβRIII mRNA has also been reported to decrease with transdifferentiation of hepatic stellate cells (HSC) to myofibroblasts [30] and during induction of EMT in a pancreatic model [16].…”

Section: Regulation Structure and Function Of The Type III Tgf-β Rementioning

confidence: 99%

Roles for the type III TGF-β receptor in human cancer

Gatza

Blobe

2010

Cellular Signalling

165

176

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Transforming growth factor β (TGF-β) superfamily ligands have important roles in regulating cellular homeostasis, embryonic development, differentiation, proliferation, immune surveillance, angiogenesis, motility, and apoptosis in a cell type and context specific manner. TGF-β superfamily signaling pathways also have diverse roles in human cancer, functioning to either suppress or promote cancer progression. The TGF-β superfamily co-receptor, the type III TGF-β receptor (TβRIII, also known as betaglycan) mediates TGF-β superfamily ligand dependent as well as ligand independent signaling to both Smad and non-Smad signaling pathways. Loss of TβRIII expression during cancer progression and direct effects of TβRIII on regulating cell migration, invasion, proliferation, and angiogenesis support a role for TβRIII as a suppressor of cancer progression and/or as a metastasis suppressor. Defining the physiological function and mechanism of TβRIII action and alterations in TβRIII function during cancer progression should enable more effective targeting of TβRIII and TβRIII mediated functions for the diagnosis and treatment of human cancer.

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Dexamethasone Enhancement of Betaglycan (TGF-β Type III Receptor) Gene Expression in Osteoblast-like Cells

Cited by 31 publications

References 0 publications

Betaglycan Expression Is Transcriptionally Up-regulated during Skeletal Muscle Differentiation

Betaglycan Expression Is Transcriptionally Up-regulated during Skeletal Muscle Differentiation

Cloning the Promoter for Transforming Growth Factor-β Type III Receptor

Roles for the type III TGF-β receptor in human cancer

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