Phosphatidylinositol 3-Kinase Stimulates Muscle Differentiation by Activating p38 Mitogen-Activated Protein Kinase

Chun, Yoon Keun; Kim, Jayoung; Kwon, Sijoong; Choi, Sanghyuk; Hong, Feng; Moon, Kuen-ai; Kim, Joung Mok; Choi, Sang Lim; Kim, Bum Shik; Ha, Joohun; Kim, Sung Soo

doi:10.1006/bbrc.2000.3486

Cited by 23 publications

(19 citation statements)

References 28 publications

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“…Although c-Ras activity remained high during differentiation in DM, Erk activity decreased to basal levels found in serum-free medium controls ( Figure 4B). In contrast, PI3K activity in differentiated cells was approximately twofold higher than that of proliferating cells, which is in accordance with previous reports [26]. Inhibition of c-Ras activity by dnRas (R1 and R2) and farnesyltransferase inhibitors (LB and FTS) significantly reduced PI3K activity, but did not affect Erk activity in DM ( Figure 4B).…”

Section: C-ras Stimulates Muscle Differentiation Via Pi3ksupporting

confidence: 92%

“…Levels of c-Ras in p110*+dnRas cells was almost twofold higher compared to p110* and control cells ( Figure 5A). Compared with mock cells, p110* cells differentiated at a much faster rate, as previously shown [26]. The p110* cells fully differentiate into multinucleated myotubes after 3 days in DM, whereas mock cells take 6 days.…”

Section: Constitutively Active Pi3k Completely Substitutes For Cras Dsupporting

confidence: 80%

“…Inhibition of c-Ras activity by dnRas (R1 and R2) and farnesyltransferase inhibitors (LB and FTS) significantly reduced PI3K activity, but did not affect Erk activity in DM ( Figure 4B). To further verify effects of PI3K, we evaluated differentiation in previously established stable cell lines expressing dominant negative PI3K (∆p85) and constitutively active PI3K (p110*) [26]. Using previously described assays, we found that inhibition of PI3K blocked muscle differentiation, while constitutively active PI3K induced differentiation ( Figure 4C-4E).…”

Section: C-ras Stimulates Muscle Differentiation Via Pi3kmentioning

confidence: 83%

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Proto-oncogenic H-Ras, K-Ras, and N-Ras are involved in muscle differentiation via phosphatidylinositol 3-kinase

et al. 2010

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Oncogenic H-Ras G12V and its variants have been shown to inhibit muscle differentiation. However, the role of proto-oncogenic Ras (c-Ras) in muscle differentiation remains unclear. The active GTP-bound form of Ras has been known to associate with diverse effectors including Raf, phosphatidylinositol 3-kinase (PI3K), Ral-GDS, and other molecules to transmit downstream signals. We hypothesize that c-Ras may stimulate muscle differentiation by selectively activating PI3K, an important mediator for muscle differentiation. In our experiments, inhibition of c-Ras by farnesyltransferase inhibitors and a dominant negative form of H-Ras (Ras S17N) suppressed muscle differentiation. Consistently, individual knockdown of H-Ras, K-Ras, and N-Ras by siRNAs all blocked muscle differentiation. Interestingly, we found that c-Ras preferentially interacts with PI3K rather than its major binding partner c-Raf, during myogenic differentiation, with total c-Ras activity remaining unchanged. PI3K and its downstream myogenic pathway, the Nox2/NF-κB/inducible nitric oxide synthase (iNOS) pathway, were found to be suppressed by inhibition of c-Ras activity during differentiation. Furthermore, expression of a constitutively active form of PI3K completely rescued the differentiation block and reactivated the Nox2/NF-κB/iNOS pathway in c-Ras-inhibited cells. On the basis of our results, we conclude that contrary to oncogenic Ras, proto-oncogenic H-Ras, K-Ras, and N-Ras are directly involved in the promotion of muscle differentiation via PI3K and its downstream signaling pathways. In addition, PI3K pathway activation is associated with a concurrent suppression of the otherwise predominantly activated Raf/ Mek/Erk pathway.

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Section: C-ras Stimulates Muscle Differentiation Via Pi3ksupporting

confidence: 92%

Section: Constitutively Active Pi3k Completely Substitutes For Cras Dsupporting

confidence: 80%

Section: C-ras Stimulates Muscle Differentiation Via Pi3kmentioning

confidence: 83%

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Proto-oncogenic H-Ras, K-Ras, and N-Ras are involved in muscle differentiation via phosphatidylinositol 3-kinase

et al. 2010

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“…Immunoreactive protein bands were measured by densitometry and corrected for ␤-actin. proliferation of myogenic progenitors/ myoblasts requires activation of the classic MAP kinase (Erk) cascade (Bennett and Tonks, 1997;Tortorella et al, 2001;Milasincic et al, 1996;Coolican et al, 1997;Chun et al, 2000;Li et al, 2000;Wu et al, 2000;Tiffin et al, 2004). It is, however, of note that the classic MAP kinase cascade exerts dual effects on myogenesis and can also promote myogenic differentiation (Gredinger et al, 1998;Sarbassov et al, 1997).…”

Section: Resultsmentioning

confidence: 99%

The chemokine SDF1 controls multiple steps of myogenesis through atypical PKCζ

Ödemis

Boosmann

Dieterlen

et al. 2007

Journal of Cell Science

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Mice deficient in the SDF1-chemokine-receptor CXCR4, exhibit severe defects of secondary limb myogenesis. To further elucidate the role of SDF1 in muscle development, we have now analyzed putative effects of this chemokine on proliferation, migration and myogenic differentiation of mouse C2C12 myogenic progenitor/myoblast cells. In addition, we have characterized the signaling pathways employed by SDF1-CXCR4 to control myogenesis. We found that SDF1 stimulates proliferation and induces migration of C2C12 cells with a potency similar to that of FGF2 and HGF, which both represent prototypical extracellular regulators of myogenesis. In addition, SDF1 inhibits myogenic differentiation in both C2C12 cells and primary myoblasts, as assessed by MyoD, myosin heavy chain and/or myogenin expression. Regarding signaling pathways, C2C12 cells responded to SDF1 with activation (phosphorylation) of Erk and PKCζ, whereas even after prolonged SDF1 treatment for up to 120 minutes, levels of activated Akt, p38 and PKCα or PKCβ remained unaffected. Preventing activation of the classic MAP kinase cascade with the Erk inhibitor UO126 abolished SDF1-induced proliferation and migration of C2C12 cells but not the inhibitory action of SDF1 on myogenic differentiation. Moreover, the effects of SDF1 on proliferation, migration and differentiation of C2C12 cells were all abrogated in the presence of myristoylated PKCζ peptide pseudosubstrate and/or upon cellular depletion of PKCζ by RNA interference. In conclusion, our findings unravel a previously unknown role of CXCR4-PKCζ signaling in myogenesis. The potent inhibitory effects of SDF1 on myogenic differentiation point to a major function of CXCR4-PKCζ signaling in the control of secondary muscle growth.

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“…Finally, non-genomic effects of T 4 have been reported (Davis et al 2002). T 4 appears to activate signal transducing kinases (Davis et al 2002), amongst them those involved in differentiation such as the mitogen-activating protein kinase pathway (Chun et al 2000).…”

Section: Thyroid Hormone Uptake In H9c2(2-1) Cells · H H a G M Van Dementioning

confidence: 99%

Uptake of tri-iodothyronine and thyroxine in myoblasts and myotubes of the embryonic heart cell line H9c2(2-1)

Putten

Joosten²,

Klaren³

et al. 2002

Journal of Endocrinology

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Uptake of tri-iodothyronine (T 3 ) was compared with that of thyroxine (T 4 ) in the embryonic heart cell line H9c2 (2-1). These cells propagate as myoblasts and form differentiated myotubes upon reduction of the serum concentration, as indicated by a 31-fold increase in creatine kinase activity. Protein and DNA content per well were around 2-fold higher in myotubes than in myoblasts. When expressed per well, T 3 and T 4 uptake were, compared with myoblasts, 1·9-to 2-fold and 3·1-to 4-fold higher in myotubes respectively. On the other hand, the characteristics of T 3 and T 4 uptake were similar in myoblasts and myotubes. At any time-point, T 4 uptake was 2-fold higher than that of T 3 , and both uptakes were energy but not Na + dependent. T 3 and T 4 uptake exhibited mutual inhibition in myoblasts and myotubes: 10 µM unlabeled T 3 reduced T 4 uptake by 51-60% (P<0·001), while 10 µM T 4 inhibited T 3 uptake by 48-51% (P<0·001). Furthermore, T 3 and T 4 uptake in myoblasts was dose-dependently inhibited by tryptophan (maximum inhibition around 70%; P<0·001). Exposure of the cells to T 3 or T 4 during differentiation significantly increased the fusion index (35 and 40%; P<0·01). Finally, both myoblasts and myotubes showed a small deiodinase type I activity, while deiodinase type II activity was undetectable. In conclusion, T 3 and T 4 share a common energy-dependent transport system in H9c2(2-1) cells, that may be important for the availability of thyroid hormone during differentiation.

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Phosphatidylinositol 3-Kinase Stimulates Muscle Differentiation by Activating p38 Mitogen-Activated Protein Kinase

Cited by 23 publications

References 28 publications

Proto-oncogenic H-Ras, K-Ras, and N-Ras are involved in muscle differentiation via phosphatidylinositol 3-kinase

Proto-oncogenic H-Ras, K-Ras, and N-Ras are involved in muscle differentiation via phosphatidylinositol 3-kinase

The chemokine SDF1 controls multiple steps of myogenesis through atypical PKCζ

Uptake of tri-iodothyronine and thyroxine in myoblasts and myotubes of the embryonic heart cell line H9c2(2-1)

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