Transforming Growth Factor β1 Is Up-regulated by Activated Raf in Skeletal Myoblasts but Does Not Contribute to the Differentiation-defective Phenotype

Wang, Xu; Thomson, Season R.; Starkey, J. D.; Page, Jeanine L.; Ealy, Alan D.; Johnson, Sally

doi:10.1074/jbc.m306489200

Cited by 13 publications

(18 citation statements)

References 47 publications

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“…It has been recently reported that high level of Raf activity, downstream target of Ras, could inhibit myogenic program through both MEK-dependent and MEK-independent signaling pathways (35). Very interestingly, TGF-h expression was upregulated in differentiation-defective myoblasts caused by high level of Raf activation (35). Together with our data from this study, it is most likely that myostatin functions through an autocrine loop to synergize Raf signaling and repress myogenesis in a more effective way.…”

Section: Discussionsupporting

confidence: 70%

“…Furthermore, using dominantnegative Ras allowed us to show that the myostatin-induced inhibition of Erk1/2 activation and proliferation was via upstream Ras. It has been recently reported that high level of Raf activity, downstream target of Ras, could inhibit myogenic program through both MEK-dependent and MEK-independent signaling pathways (35). Very interestingly, TGF-h expression was upregulated in differentiation-defective myoblasts caused by high level of Raf activation (35).…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

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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“…This phenomenon could have been caused by receptor downregulation events associated with ligand overloading (Murono et al 1993). Alternatively, this effect could reflect differential receptor usage that could have prompted secondary signaling systems that interfered with the primary signaling response (Wang et al 2004, Garcia-Maya et al 2006, Hayashi et al 2008.…”

Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor 10 enhances bovine oocyte maturation and developmental competence in vitro

Zhang¹,

Hansen²,

Ealy³

2010

Reproduction

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The ability of oocytes to resume meiosis, become fertilized, and generate viable pregnancies is controlled during folliculogenesis by several endocrine and paracrine factors. The aim of this work is to determine whether fibroblast growth factor 10 (FGF10) is an oocyte competent factor. Transcripts for each of the four FGF receptor types (FGFR) were present in cumulus and oocytes after their extraction from the follicles. FGFR1 transcripts predominated in cumulus cells whereas FGFR2 was most abundant in oocytes. Exposing the cumulus-oocyte complexes to FGF10 during in vitro maturation did not affect cleavage rates, but increases (P!0.05) in the percentage of embryos at the 8-16-cell stage on day 3 and at the blastocyst stage on day 7, which were evident in FGF10-supplemented oocytes. The progression of oocytes through meiosis and cumulus expansion was increased (P!0.05) by FGF10. The importance of the endogenous sources of FGFs was examined by adding anti-FGF10 IgG during oocyte maturation. Blocking endogenous FGF10 activity decreased (P!0.05) the percentage of oocytes developing into blastocysts and limited (P!0.05) cumulus expansion. Expression profiles of putative cumulus and oocyte competency markers were examined for their involvement in FGF10-mediated responses. FGF10 influenced the expression of CTSB and SPRY2 in cumulus cells and BMP15 in oocytes. In summary, this work provides new insight into the importance of FGFRs and locally derived FGF10 during oocyte maturation in cattle. Its subsequent impact on in vitro embryo development implicates it as a noteworthy oocyte competent factor.

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“…Many tumors disable TGFb signaling by downregulation or mutation of the TGFb receptor, or through inactivation of its downstream targets SMAD4, p15 INK4B and the retinoblastoma protein Rb (Hanahan and Weinberg, 2000). Activation of Raf and ERK induces TGFb production but at the same time protects cells from differentiation and apoptosis (Lehmann et al, 2000;Park et al, 2000;Schulze et al, 2001Schulze et al, , 2004Wang et al, 2004;Riesco-Eizaguirre et al, 2009), enabling them to draw on the pro-tumorigenic effects of this cytokine such as promotion of proliferation, invasiveness, radioresistance and immunosuppression.…”

Section: Raf and The Hallmarks Of Cancermentioning

confidence: 99%

Raf kinases in cancer–roles and therapeutic opportunities

2011

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Raf are conserved, ubiquitous serine/protein kinases discovered as the cellular elements hijacked by transforming retroviruses. The three mammalian RAF proteins (A, B and CRAF) can be activated by the human oncogene RAS, downstream from which they exert both kinase-dependent and kinase-independent, tumor-promoting functions. The kinase-dependent functions are mediated chiefly by the MEK/ERK pathway, whose activation is associated with proliferation in a broad range of human tumors. Almost 10 years ago, activating BRAF mutations were discovered in a subset of human tumors, and in the past year treatment with small-molecule RAF inhibitors has yielded unprecedented response rates in melanoma patients. Thus, Raf qualifies as an excellent molecular target for anticancer therapy. This review focuses on the role of BRAF and CRAF in different aspects of carcinogenesis, on the success of molecular therapies targeting Raf and the challenges they present.

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Transforming Growth Factor β1 Is Up-regulated by Activated Raf in Skeletal Myoblasts but Does Not Contribute to the Differentiation-defective Phenotype

Cited by 13 publications

References 47 publications

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

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

Fibroblast growth factor 10 enhances bovine oocyte maturation and developmental competence in vitro

Raf kinases in cancer–roles and therapeutic opportunities

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