Smad1 and Smad5 Act Downstream of Intracellular Signalings of BMP-2 That Inhibits Myogenic Differentiation and Induces Osteoblast Differentiation in C2C12 Myoblasts

Yamamoto, Naoya; Akiyama, Shinichiro; Katagiri, Takenobu; Namiki, Mana; Kurokawa, Takahide; Suda, Toshio

doi:10.1006/bbrc.1997.7325

Cited by 205 publications

(144 citation statements)

References 43 publications

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“…Moreover, the overexpression in the myoblasts of Smad7, which is known to block the TGF-␤-dependent phosphorylation and translocation to the nucleus of Smad2 and -3, did not modify the negative effect of TGF-␤ on IGFBP-5 induction and differentiation. Our observations differ significantly from those recently reported by Yamamoto et al (52). These authors demonstrated that overexpression of Smad2 and Smad3 which was supposed to mimic TGF-␤ actions, specifically blocked myogenin promoter activity in C2C12 myoblasts cultured in differentiation medium.…”

Section: Figcontrasting

confidence: 99%

Transforming Growth Factor-β Inhibition of Insulin-like Growth Factor-binding Protein-5 Synthesis in Skeletal Muscle Cells Involves a c-Jun N-terminal Kinase-dependent Pathway

Rousse

Lallemand

Montarras

et al. 2001

Journal of Biological Chemistry

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Transforming growth factor-␤ (TGF-␤) and insulin-like growth factors (IGFs) play critical roles in the control of myogenesis. Insulin-like growth factor-binding protein-5 (IGFBP-5), by regulating the bioavailability of IGFs, is involved in controlling IGF-dependent differentiation. We investigated the effects of TGF-␤ on the IGFBP-5 production induced by IGFs in mouse myoblasts. TGF-␤ leads to a decrease in IGFBP-5 synthesis at both transcript and protein levels, and blocked muscle differentiation. The Smad proteins and the c-Jun N-terminal kinase (JNK) have been shown to be involved in TGF-␤ signaling pathways. We provide evidence that the JNK pathway, rather than Smad proteins, is involved in the response of muscle cells to TGF-␤. This factor failed to stimulate the GAL4-Smad 2/3 transcriptional activities of the constructs used to transfect myoblasts. Moreover, stable expression of the antagonistic Smad7 did not abolish the inhibitory effect of TGF-␤ on IGFBP-5 production whereas expression of a dominant-negative version of MKK4, an upstream activator of JNK, did. We also showed, using a specific inhibitor, that the p38 mitogen-activated protein kinase (p38 MAPK) was not involved in the inhibition of IGFBP-5 production. Thus, TGF-␤-mediated IGFBP-5 inhibition is independent of Smads and requires activation of the JNK signaling pathway.

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Section: Figcontrasting

confidence: 99%

Transforming Growth Factor-β Inhibition of Insulin-like Growth Factor-binding Protein-5 Synthesis in Skeletal Muscle Cells Involves a c-Jun N-terminal Kinase-dependent Pathway

Rousse

Lallemand

Montarras

et al. 2001

Journal of Biological Chemistry

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“…The identification of the involvement of BMP receptors (6), intracellular mediator Smads (8,9) and osteogenic master transcription factor, Runx2 (12), was important for our understanding in BMP-2-induced osteogenic transdifferentiation of myogenic cells in vitro (3) and ectopic bone formation in muscle tissue (1). Despite the information available regarding the role of individual components in this differentiation model, we still do not have a complete picture integrating BMP-signaling molecules and the key transcription factors.…”

Section: Discussionmentioning

confidence: 99%

“…BMPR-I is further subclassified into BMPR-IA (also called ALK3) and BMPR-IB (also called ALK6). It has been shown that both the inhibition of myoblast differentiation and the induction of osteoblast differentiation by BMP-2 involve the activations of BMPR-I receptors (6,7), their intracellular transducers Smad1 and Smad5 (8,9), and the osteogenic master transcription factor Runx2 (4,10).…”

mentioning

confidence: 99%

BMP-2-induced Runx2 Expression Is Mediated by Dlx5, and TGF-β1 Opposes the BMP-2-induced Osteoblast Differentiation by Suppression of Dlx5 Expression

Lee

Kim

et al. 2003

Journal of Biological Chemistry

385

329

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“…Although overexpression of either Smad1 or Smad5 in C2C12 cells leads to an osteoblast phenotype (27,30,33), Smad5 may normally play a more prominent role in mediating the BMP signaling in certain cells as suggested by the genetic analyses of Smad1 or Smad5 null mice (34).…”

Section: Discussionmentioning

confidence: 99%

Smurf1 Facilitates Myogenic Differentiation and Antagonizes the Bone Morphogenetic Protein-2-induced Osteoblast Conversion by Targeting Smad5 for Degradation

Ying

Hussain

Zhang

2003

Journal of Biological Chemistry

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Controlled proteolysis mediated by Smad ubiquitination regulatory factors (Smurfs) plays a crucial role in modulating cellular responses to signaling of the transforming growth factor-␤ (TGF-␤) superfamily. However, it is not clear what influences the selectivity of Smurfs in the individual signaling pathway, nor is it clear the biological function of Smurfs in vivo. Using a mouse C2C12 myoblast cell differentiation system, which is subject to control by both TGF-␤ and bone morphogenetic protein (BMP), here we examine the role of Smurf1 in myogenic differentiation. We show that increased expression of Smurf1 promotes myogenic differentiation of C2C12 cells and blocks the BMP-induced osteogenic conversion but has no effect on the TGF-␤-induced differentiation arrest. Consistent with an inhibitory role in the BMP signaling pathway, the elevated Smurf1 markedly reduces the level of endogenous Smad5, whereas it leaves unaltered that of Smad2, Smad3, and Smad7, which are components of the TGF-␤ pathway. Adding back Smad5 from a different source to the Smurf1-overexpressing cells restores the BMP-mediated osteoblast conversion. Finally, by depletion of the endogenous Smurf1 through small interfering RNA-mediated RNA interference, we demonstrate that Smurf1 is required for the myogenic differentiation of C2C12 cells and plays an important regulatory role in the BMP-2-mediated osteoblast conversion.Smad proteins are principal intracellular signaling mediators of the TGF-␤ 1 superfamily of peptide growth factors that regulate a wide range of biological processes (1-3). As such, controlling Smad activity and protein levels are crucial for proper signaling by TGF-␤ and its related factors. Recent discoveries of Smad ubiquitination regulatory factors (Smurfs), which are members of the HECT domain family of ubiquitin ligases, have implicated a role of the ubiquitination-mediated protein degradation in the signaling pathways of TGF-␤ superfamily (4 -7). Ubiquitination is a covalent attachment of a chain of the highly conserved, 76-amino acid ubiquitin to selected targets, which are subsequently degraded in the 26 S proteasomes (8, 9). This process is catalyzed by sequential actions of three enzymes, the E1 ubiquitin activating enzyme, the E2 ubiquitin-conjugating enzyme, and the E3 ubiquitin ligase. Ubiquitin ligases physically interact with protein substrates, therefore playing a central role in determining substrate specificity. Despite several reports of biochemical evidence for the Smurf-mediated degradation of Smads, important questions remain with regard to the biological significance of this regulation and the specificity of Smurf action.Signaling by the TGF-␤ superfamily of peptide growth factors is mediated by a complex of two types of transmembrane serine/threonine kinase receptors and the intracellular Smad proteins (for reviews, see Refs. 1-3). Three classes of Smads have been defined based on their differences in sequence and function: the receptor-regulated Smads (R-Smads), the common Smad (Smad4), and the inhib...

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Smad1 and Smad5 Act Downstream of Intracellular Signalings of BMP-2 That Inhibits Myogenic Differentiation and Induces Osteoblast Differentiation in C2C12 Myoblasts

Cited by 205 publications

References 43 publications

Transforming Growth Factor-β Inhibition of Insulin-like Growth Factor-binding Protein-5 Synthesis in Skeletal Muscle Cells Involves a c-Jun N-terminal Kinase-dependent Pathway

Transforming Growth Factor-β Inhibition of Insulin-like Growth Factor-binding Protein-5 Synthesis in Skeletal Muscle Cells Involves a c-Jun N-terminal Kinase-dependent Pathway

BMP-2-induced Runx2 Expression Is Mediated by Dlx5, and TGF-β1 Opposes the BMP-2-induced Osteoblast Differentiation by Suppression of Dlx5 Expression

Smurf1 Facilitates Myogenic Differentiation and Antagonizes the Bone Morphogenetic Protein-2-induced Osteoblast Conversion by Targeting Smad5 for Degradation

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