Differential signaling through NFκB does not ameliorate skeletal myoblast apoptosis during differentiation

Dee, K; DeChant, Anne; Weyman, Crystal M.

doi:10.1016/s0014-5793(03)00571-4

Cited by 8 publications

(13 citation statements)

References 49 publications

(91 reference statements)

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“…These data suggested that the ability of S100B to protect myoblasts against apoptosis and to stimulate myoblast proliferation relied on a single pathway, the Ras-MEK-ERK1/2 pathway that converged onto two different downstream targets that is NF-kB and Rb, respectively. In this regard, it was shown that proliferation arrest and apoptosis in myoblasts cultivated in DM are two separate events (Dee et al, 2003). Remarkably, the ability of S100B to induce cyclin D1 expression was manifest at as low as 10 pM (Fig.…”

Section: S100b Stimulates Myoblast Proliferation Via Ras-mek-erk1/2 Amentioning

confidence: 88%

S100B stimulates myoblast proliferation and inhibits myoblast differentiation by independently stimulating ERK1/2 and inhibiting p38 MAPK

Riuzzi

Sorci

Donato

2006

Journal Cellular Physiology

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The Ca2+-modulated protein of the EF-hand type, S100B, was shown to inhibit rat L6 myoblast differentiation and myotube formation by interacting with a high affinity with an unidentified receptor (Sorci et al., 2003). We show here that S100B independently inhibits the MKK6-p38 MAPK pathway and stimulates the Ras-MEK-ERK1/2 pathway. The inhibitory effect of S100B on p38 MAPK translates into a defective induction of the muscle-specific transcription factor myogenin and the antiproliferative factor p21(WAF1), while S100B's stimulatory effect on ERK1/2 results in stimulation of myoblast proliferation via cyclin D1 induction and Rb phosphorylation and protection against apoptosis via activation of NF-kappaB transcriptional activity. Also, the S100B's effects that are mediated by the Ras-MEK-ERK1/2 pathway that is, stimulation of proliferation and protection against apoptosis, depend on reactive oxygen species production, being inhibited by antioxidants, while the S100B inhibitory effect on the MKK6-p38 MAPK pathway is not. We propose that S100B might participate in the regulation of myoblast differentiation by stimulating myoblast proliferation, protecting myoblasts against apoptosis, and modulating myotube formation.

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Section: S100b Stimulates Myoblast Proliferation Via Ras-mek-erk1/2 Amentioning

confidence: 88%

S100B stimulates myoblast proliferation and inhibits myoblast differentiation by independently stimulating ERK1/2 and inhibiting p38 MAPK

Riuzzi

Sorci

Donato

2006

Journal Cellular Physiology

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“…Differentiation was induced and monitored after switching cells from growth medium to differentiation medium (DM), which consists of BME, 1% P/S and 0% FBS [4,[20][21][22][23][28][29][30][31]. Cells were incubated at 37°C in 5% CO 2 .…”

Section: Cells and Cell Culturementioning

confidence: 99%

“…Despite the wealth of molecular knowledge detailing skeletal myoblast determination and differentiation, information regarding the molecular mechanisms controlling the apoptosis associated with skeletal myoblast differentiation is limited [3,4,[17][18][19][20][21][22][23][24]. The molecular mechanisms responsible for apoptosis in other systems, however, have been extensively studied.…”

Section: Introductionmentioning

confidence: 99%

Increased expression of the pro-apoptotic Bcl2 family member PUMA is required for mitochondrial release of cytochrome C and the apoptosis associated with skeletal myoblast differentiation

et al. 2007

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We have previously shown that when skeletal myoblasts are cultured in differentiation medium (DM), roughly 30% undergo caspase 3-dependent apoptosis rather than differentiation. Herein, we investigate the molecular mechanism responsible for the activation of caspase 3 and the ensuing apoptosis. When 23A2 myoblasts are cultured in DM, caspase 9 activity is increased and pharmacological abrogation of caspase 9 activation impairs caspase 3 activation and apoptosis. Further, we detect a time dependent release of mitochondrial cytochrome C into the cytosol in roughly 30% of myoblasts. Inclusion of cycloheximide inhibits the release of cytochrome C, the activation of caspase 9 and apoptosis. These data indicate that the mitochondrial pathway plays a role in this apoptotic process and that engagement of this pathway relies on de novo protein synthesis. Through RT-PCR and immunoblot analysis, we have determined that the expression level of the pro-apoptotic Bcl2 family member PUMA is elevated when 23A2 myoblasts are cultured in DM. Further, silencing of PUMA inhibits the release of cytochrome C and apoptosis. Signaling by the transcription factor p53 is not responsible for the increased level of PUMA. Finally, myoblasts rescued from apoptosis by either inhibition of elevated caspase 9 activity or silencing of PUMA are competent for differentiation. These results indicate a critical role for PUMA in the apoptosis associated with skeletal myoblast differentiation and that a p53-independent mechanism is responsible for the increased expression of PUMA in these cells.

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“…The PI3-kinase/Akt pathway, the Raf/MEK/MAPK pathway, and the NFkB pathway remain the best characterized downstream targets of activated Ras (Finco et al, 1997;Ramirez De Molina et al, 2004;White et al, 1995). We have previously reported that both signaling through MEK and NFkB (Dee et al, 2003) are constitutively active in 23A2 myoblasts expressing G12V:H-Ras. Herein, we report that signaling through PI3-kinase is constitutive in myoblasts expressing either G12V:H-Ras.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously demonstrated that inhibiting either MEK/MAPK or NFkB (Dee et al, 2003) does not revert the G12V:H-Ras-induced effect on differentiation and the associated apoptosis. Furthermore, simultaneous inhibition of PI3-kinase, rapamycin, MEK and NFkB and does not restore the ability of G12V:H-Ras-expressing myoblasts to differentiate or undergo the associated apoptosis ( Fig.…”

Section: Constitutive Pi3-kinase Signaling Is Not Required For the Acmentioning

confidence: 99%

Active Ras‐induced effects on skeletal myoblast differentiation and apoptosis are independent of constitutive PI3‐kinase activity

Karasarides

Dee

Schulman

et al. 2006

Cell Biology International

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23A2 myoblasts expressing GAP-resistant, constitutively active G12V:H-Ras (A2:G12V:H-Ras myoblasts) display a transformed morphology and do not undergo mitogen-deprivation-induced differentiation or the associated apoptosis. To determine the phenotype induced by F156L:H-Ras, a constitutively active mutant with enhanced nucleotide exchange activity rather than impaired GAP-stimulated GTPase activity, myoblast cell lines were established that stably express F156L:H-Ras at levels of H-Ras comparable to the A2:G12V:H-Ras myoblasts. These A2:F156L:H-Ras myoblast cell lines do not possess a transformed morphology, and while differentiation and apoptosis are impaired, these processes are not abrogated as in the A2:G12V:H-Ras myoblasts. Surprisingly, while expression of either G12V:H-Ras or F156L:H-Ras results in constitutive signaling through PI3-kinase, only cells expressing G12V:H-Ras additionally possess constitutive signaling through MAPK, and NFkappaB. Pharmacological abrogation of the Ras-induced constitutive PI3-kinase signal, however, is not responsible for the impaired differentiation or apoptosis in either A2:G12V:H-Ras myoblasts or A2:F156L:H-Ras myoblasts. Thus, our data suggest that a pathway distinct from those that signals through MAPK, NFkappaB or PI3-kinase is responsible for the impaired differentiation and apoptosis in 23A2 skeletal myoblasts expressing constitutively active Ras.

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Differential signaling through NFκB does not ameliorate skeletal myoblast apoptosis during differentiation

Cited by 8 publications

References 49 publications

S100B stimulates myoblast proliferation and inhibits myoblast differentiation by independently stimulating ERK1/2 and inhibiting p38 MAPK

S100B stimulates myoblast proliferation and inhibits myoblast differentiation by independently stimulating ERK1/2 and inhibiting p38 MAPK

Increased expression of the pro-apoptotic Bcl2 family member PUMA is required for mitochondrial release of cytochrome C and the apoptosis associated with skeletal myoblast differentiation

Active Ras‐induced effects on skeletal myoblast differentiation and apoptosis are independent of constitutive PI3‐kinase activity

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