Myostatin inhibits rhabdomyosarcoma cell proliferation through an Rb-independent pathway

Langley, Brett; Thomas, Mark; McFarlane, Craig; Gilmour, Stewart; Sharma, Mridula; Kambadur, Ravi

doi:10.1038/sj.onc.1207144

Cited by 50 publications

(44 citation statements)

References 57 publications

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“…Myostatin has also been implicated in the regulation of satellite cell activation, proliferation, and self-renewal that accompanies the up-regulation of p21 Waf1,Cip1 (11). However, work by Langley et al (12) showed that myostatin treatment inhibited rhabdomyosarcoma cell proliferation through an Rb-independent mechanism. Therefore, the antiproliferative effects of myostatin could be achieved by utilization of multisignal pathways.…”

mentioning

confidence: 92%

Myostatin Induces Cyclin D1 Degradation to Cause Cell Cycle Arrest through a Phosphatidylinositol 3-Kinase/AKT/GSK-3β Pathway and Is Antagonized by Insulin-like Growth Factor 1

Yang

Zhang

et al. 2007

Journal of Biological Chemistry

198

158

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Myostatin is a transforming growth factor ␤ superfamily member and is known as an inhibitor of skeletal muscle cell proliferation and differentiation. Exposure to myostatin induces G 1 phase cell cycle arrest. In this study, we demonstrated that myostatin down-regulates Cdk4 activity via promotion of cyclin D1 degradation. Overexpression of cyclin D1 significantly blocked myostatin-induced proliferation inhibition. We further showed that phosphorylation at threonine 286 by GSK-3␤ was required for myostatin-stimulated cyclin D1 nuclear export and degradation. This process is dependent upon the activin receptor IIB and the phosphatidylinositol 3-kinase/ Akt pathway but not Smad3. Insulin-like growth factor 1 (IGF-1) treatment or Akt activation attenuated the myostatin-stimulated cyclin D1 degradation as well as the associated cell proliferation repression. In contrast, attenuation of IGF-1 signaling caused C2C12 cells to undergo apoptosis in response to myostatin treatment. The observation that IGF-1 treatment increases myostatin expression through a phosphatidylinositol 3-kinase pathway suggests a possible feedback regulation between IGF-1 and myostatin. These findings uncover a novel role for myostatin in the regulation of cell growth and cell death in concert with IGF-1.

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mentioning

confidence: 92%

Myostatin Induces Cyclin D1 Degradation to Cause Cell Cycle Arrest through a Phosphatidylinositol 3-Kinase/AKT/GSK-3β Pathway and Is Antagonized by Insulin-like Growth Factor 1

Yang

Zhang

et al. 2007

Journal of Biological Chemistry

198

158

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“…Loss of myostatin results in increased muscle growth due to increased SC number and activation [8]. Furthermore, myoblasts derived from myostatinnull SCs show increased proliferation and enhanced differentiation [12,36]. In contrast, increased levels of myostatin have been shown to inhibit myoblast proliferation, arresting cells at the G 1 to S transition, further resulting in reduced differentiation [7].…”

Section: Muscle Atrophy Seen In Smad3-null Muscles Could Be Due To Inmentioning

confidence: 99%

Smad3 signaling is required for satellite cell function and myogenic differentiation of myoblasts

McFarlane

Vajjala

et al. 2011

Cell Res

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TGF-β and myostatin are the two most important regulators of muscle growth. Both growth factors have been shown to signal through a Smad3-dependent pathway. However to date, the role of Smad3 in muscle growth and differentiation is not investigated. Here, we demonstrate that Smad3-null mice have decreased muscle mass and pronounced skeletal muscle atrophy. Consistent with this, we also find increased protein ubiquitination and elevated levels of the ubiquitin E3 ligase MuRF1 in muscle tissue isolated from Smad3-null mice. Loss of Smad3 also led to defective satellite cell (SC) functionality. Smad3-null SCs showed reduced propensity for self-renewal, which may lead to a progressive loss of SC number. Indeed, decreased SC number was observed in skeletal muscle from Smad3-null mice showing signs of severe muscle wasting. Further in vitro analysis of primary myoblast cultures identified that Smad3-null myoblasts exhibit impaired proliferation, differentiation and fusion, resulting in the formation of atrophied myotubes. A search for the molecular mechanism revealed that loss of Smad3 results in increased myostatin expression in Smad3-null muscle and myoblasts. Given that myostatin is a negative regulator, we hypothesize that increased myostatin levels are responsible for the atrophic phenotype in Smad3-null mice. Consistent with this theory, inactivation of myostatin in Smad3-null mice rescues the muscle atrophy phenotype.

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“…Further investigation showed that the myostatin-stimulated cell cycle arrest was probably due to an increased expression of cyclin-dependent kinase (Cdk) inhibitor p21 Waf1,Cip1 and a decreased cyclin E/Cdk2 activity, which further caused the hypophosphorylation of Rb protein (11). It was also reported that myostatin inhibited rhabdomyosarcoma cell proliferation through an Rb-independent pathway (12). MyoD and myogenin were implicated to participate in myostatin-induced differentiation suppression (10).…”

Section: Introductionmentioning

confidence: 99%

Extracellular Signal–Regulated Kinase 1/2 Mitogen-Activated Protein Kinase Pathway Is Involved in Myostatin-Regulated Differentiation Repression

et al. 2006

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The cytokines of transforming growth factor B (TGF-B) and its superfamily members are potent regulators of tumorigenesis and multiple cellular events. Myostatin is a member of TGF-B superfamily and plays a negative role in the control of cell proliferation and differentiation. We now show that myostatin rapidly activated the extracellular signal-regulated kinase 1/2 (Erk1/2) cascade in C2C12 myoblasts. A more remarkable Erk1/2 activation stimulated by myostatin was observed in differentiating cells than proliferating cells. The results also showed that Ras was the upstream regulator and participated in myostatin-induced Erk1/2 activation because the expression of a dominant-negative Ras prevented myostatin-mediated inhibition of Erk1/2 activation and proliferation. Importantly, the myostatin-suppressed myotube fusion and differentiation marker gene expression were attenuated by blockade of Erk1/2 mitogen-activated protein kinase (MAPK) pathway through pretreatment with MAPK/ Erk kinase 1 (MEK1) inhibitor PD98059, indicating that myostatin-stimulated activation of Erk1/2 negatively regulates myogenic differentiation. Activin receptor type IIb (ActRIIb) was previously suggested as the only type II membrane receptor triggering myostatin signaling. In this study, by using synthesized small interfering RNAs and dominant-negative ActRIIb, we show that myostatin failed to stimulate Erk1/2 phosphorylation and could not inhibit myoblast differentiation in ActRIIb-knockdown C2C12 cells, indicating that ActRIIb was required for myostatin-stimulated differentiation suppression. Altogether, our findings in this report provide the first evidence to reveal functional role of the Erk1/2 MAPK pathway in myostatin action as a negative regulator of muscle cell growth. (Cancer Res 2006; 66(3): 1320-6)

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Myostatin inhibits rhabdomyosarcoma cell proliferation through an Rb-independent pathway

Cited by 50 publications

References 57 publications

Myostatin Induces Cyclin D1 Degradation to Cause Cell Cycle Arrest through a Phosphatidylinositol 3-Kinase/AKT/GSK-3β Pathway and Is Antagonized by Insulin-like Growth Factor 1

Myostatin Induces Cyclin D1 Degradation to Cause Cell Cycle Arrest through a Phosphatidylinositol 3-Kinase/AKT/GSK-3β Pathway and Is Antagonized by Insulin-like Growth Factor 1

Smad3 signaling is required for satellite cell function and myogenic differentiation of myoblasts

Extracellular Signal–Regulated Kinase 1/2 Mitogen-Activated Protein Kinase Pathway Is Involved in Myostatin-Regulated Differentiation Repression

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