TGF‐β regulation of nuclear proto‐oncogenes and TGF‐β gene expression in normal human osteoblast‐like cells

Subramaniam, Malayannan; Oursler, Merry Jo; Rasmussen, K.; Riggs, B. Lawrence; Spelsberg, T. C.

doi:10.1002/jcb.240570107

Cited by 29 publications

(22 citation statements)

References 52 publications

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“…Although TGF-␤ regulates the activities of most of the AP-1 members, c-Jun activity is not altered by TGF-␤. The lack of stimulation of c-Jun by TGF-␤ has also been reported earlier in HOB, in which TGF-␤ actually reduces c-Jun mRNA level (31). Although transgenic mice overexpressing ⌬FosB have elevated FIG.…”

Section: Fig 11mentioning

confidence: 73%

“…These combined data suggest that one or more Smad-independent signaling mechanisms also mediate TGF-␤ and BMP-2 activity. In osteoblasts, both BMP-2 and TGF-␤ stimulate the expression of c-Fos, an AP-1 component (31)(32)(33). Because Ras is the upstream effector of Fos and MAPK, and AP-1-responsive element is present in the promoters of major bone matrix proteins such as type I collagen, osteocalcin, osteopontin, and fibronectin, the induction of Ras/MAPK/AP-1 appears to be an important signal transduction pathway in mediating part of the effects of BMP-2 and TGF-␤ in osteoblasts.…”

mentioning

confidence: 99%

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Signal Transductions Induced by Bone Morphogenetic Protein-2 and Transforming Growth Factor-β in Normal Human Osteoblastic Cells

Lai

Cheng

2002

Journal of Biological Chemistry

212

163

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Section: Fig 11mentioning

confidence: 73%

mentioning

confidence: 99%

Signal Transductions Induced by Bone Morphogenetic Protein-2 and Transforming Growth Factor-β in Normal Human Osteoblastic Cells

Lai

Cheng

2002

Journal of Biological Chemistry

212

163

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“…4C). On the other hand, the proliferation of human osteoblastic MG-63 cells (22), which were cocultured with R218H CED fibroblasts, was accelerated, and this acceleration was attenuated by treatment of dexamethasone (Fig. 4D).…”

Section: Domain-specific Mutations In ␤1-lap Results In Ced 11471mentioning

confidence: 98%

Domain-specific Mutations of a Transforming Growth Factor (TGF)-β1 Latency-associated Peptide Cause Camurati-Engelmann Disease Because of the Formation of a Constitutively Active Form of TGF-β1

Saito¹,

Kinoshita²,

Yoshiura³

et al. 2001

Journal of Biological Chemistry

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Transforming growth factor (TGF)-␤1 is secreted as a latent form, which consists of its mature form and a latency-associated peptide (␤1-LAP) in either the presence or the absence of additional latent TGF-␤1-binding protein. We recently reported that three different missense mutations (R218H, R218C, and C225R) of ␤1-LAP cause the Camurati-Engelmann disease (CED), an autosomal dominant disorder characterized by hyperosteosis and sclerosis of the diaphysis of the long bones. Pulse-chase experiments using fibroblasts from CED patients and expression experiments of the mutant genes in an insect cell system suggest that these mutations disrupt the association of ␤1-LAP and TGF-␤1 and the subsequent release of the mature TGF-␤1. Furthermore, the cell growth of fibroblasts from a CED patient and mutant gene-transfected fibroblasts was suppressed via TGF-␤1. The growth suppression observed was attenuated by neutralizing antibody to TGF-␤1 or by treatment of dexamethasone. On the other hand, the proliferation of human osteoblastic MG-63 cells was accelerated by coculture with CED fibroblasts. These data suggest that the domain-specific mutations of ␤1-LAP result in a more facile activation of TGF-␤1, thus causing CED. Transforming growth factor-␤1 (TGF-␤1)1 is a multifunctional protein acting on cell growth, differentiation, and morphogenesis of many different-type cells. In skeletal tissue, TGF-␤1 serves as a systematic regulator that couples bone formation and resorption by regulating the function of the osteoblasts and osteoclasts (1-5).The mature form of TGF-␤1 is proteolytically cleaved from the N-terminal remnant of the TGF-␤1 precursor, designated as TGF-␤1 latency-associated peptide (␤1-LAP) but remains non-covalently associated with the rest of the complex, which plays a role in latency of TGF-␤1 (6). TGF-␤1 is ubiquitously distributed, and the activation of the latent form is likely an important step, because it exists as either a large latent form, composed of ␤1-LAP, TGF-␤1, and latent TGF-␤1-binding protein (LTBP), or a small latent form, which is devoid of LTBP (7). Under normal conditions, activation of the latent TGF-␤1 is strictly controlled as follows. The large latent form is temporarily converted to the small latent form, which is then cleaved by plasmin or the plasmin-like protease to give the mature TGF-␤1 (6, 8, 9).Camurati-Engelmann disease (CED) or progressive diaphyseal dysplasia (DPD1) is an autosomal dominant disorder that is characterized by hyperosteosis and sclerosis of the diaphysis of the long bones (10). The onset of CED is often during early childhood with severe pain in the legs, muscle weakness, a waddling gait, and easy fatigability. The patients occasionally suffer from systemic manifestations, such as anemia, leukopenia, or hepatosplenomegaly (11). We, as well as two other groups, previously assigned the locus for CED to chromosome 19q13. 1-q13.3 (12-14). By a positional candidate gene approach and haplotype analyses, three different missense mutations (R218H, R218C, and C225R), wh...

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“…An increase in c-Jun mRNA level has been previously observed within 15 to 30 min of TGF-␤ treatment in a variety of cell types (24,39,49). In order to confirm the induction of endogenous c-Jun by TGF-␤, we performed Northern analysis of RNA and Western analysis of nuclear extracts isolated from similarly treated cells.…”

Section: Tgf-␤ Treatment Induces Dna Binding Of a Smad3-andmentioning

confidence: 96%

Smad3-Smad4 and AP-1 Complexes Synergize in Transcriptional Activation of the c-Jun Promoter by Transforming Growth Factor β

Wong

Rougier-Chapman

Frederick

et al. 1999

Molecular and Cellular Biology

257

205

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Transcriptional regulation by transforming growth factor ␤ (TGF-␤) is a complex process which is likely to involve cross talk between different DNA responsive elements and transcription factors to achieve maximal promoter activation and specificity. Here, we describe a concurrent requirement for two discrete responsive elements in the regulation of the c-Jun promoter, one a binding site for a Smad3-Smad4 complex and the other an AP-1 binding site. The two elements are located 120 bp apart in the proximal c-Jun promoter, and each was able to independently bind its corresponding transcription factor complex. The effects of independently mutating each of these elements were nonadditive; disruption of either sequence resulted in complete or severe reductions in TGF-␤ responsiveness. This simultaneous requirement for two distinct and independent DNA binding elements suggests that Smad and AP-1 complexes function synergistically to mediate TGF-␤-induced transcriptional activation of the c-Jun promoter.

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TGF‐β regulation of nuclear proto‐oncogenes and TGF‐β gene expression in normal human osteoblast‐like cells

Cited by 29 publications

References 52 publications

Signal Transductions Induced by Bone Morphogenetic Protein-2 and Transforming Growth Factor-β in Normal Human Osteoblastic Cells

Signal Transductions Induced by Bone Morphogenetic Protein-2 and Transforming Growth Factor-β in Normal Human Osteoblastic Cells

Domain-specific Mutations of a Transforming Growth Factor (TGF)-β1 Latency-associated Peptide Cause Camurati-Engelmann Disease Because of the Formation of a Constitutively Active Form of TGF-β1

Smad3-Smad4 and AP-1 Complexes Synergize in Transcriptional Activation of the c-Jun Promoter by Transforming Growth Factor β

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