Insulin Antiapoptotic Signaling Involves Insulin Activation of the Nuclear Factor κB-dependent Survival Genes Encoding Tumor Necrosis Factor Receptor-associated Factor 2 and Manganese-superoxide Dismutase

Bertrand, F; Desbois-Mouthon, Christèle; Cadoret, Axelle; Prunier, Céline; Robin, Hélène; Capeau, Jacqueline; Atfi, Azeddine; Cherqui, Gisèle

doi:10.1074/jbc.274.43.30596

Cited by 49 publications

(26 citation statements)

References 36 publications

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“…Insulin treatment rescued from PD-induced apoptosis, indicating that insulin was necessary for survival of C2Ras myoblasts in culture, in a similar fashion to that in transformed brown adipocytes (Navarro et al, 1999). Insulin anti-apoptotic e ect in C2Ras myoblasts probably depends on Mn-SOD expression, as has been previously demonstrated in CHO cells (Bertrand et al, 1999). Accordingly, treatment for 96 h with insulin and PD constitutes a di erentiation protocol for C2Ras transformed cells, producing growth arrest and inducing the formation of myotubes and the expression of Figure 6 A constitutively active AKT construct transiently transfected to C2ras myoblasts induces di erentiation in the presence of PD in an AKT/P70S6K/p38-MAPK-dependent manner.…”

Section: Discussionsupporting

confidence: 66%

“…DNA from cells cultured only in the presence of PD appeared cleaved into a ladder, this DNA degradation was not observed in the presence of insulin ( Figure 3c). Manganese-superoxide dismutase (Mn-SOD) has been described as an enzyme related to insulin survival e ect for several cell types (Bertrand et al, 1999). The expression of this protein was barely detectable for untreated cells, while C2Ras myotubes expressed Mn-SOD at both the mRNA and protein levels after treatment with insulin+PD ( Figure 3d).…”

Section: Ras-transformed C2c12 Myoblasts Fail To Differentiate In Lowmentioning

confidence: 96%

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Insulin restores differentiation of Ras-transformed C2C12 myoblasts by inducing NF-κB through an AKT/P70S6K/p38-MAPK pathway

et al. 2002

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v-H-ras transformed C2C12 (C2Ras) myoblasts, overexpressing p21-Ras protein in the Ras-GTP active form, showed a di erentiation-defective phenotype when cultured in low serum as compared with C2C12 myoblasts. Accordingly, the purpose of the present study was to delineate the signaling pathways that restore C2Ras myoblasts di erentiation. Inhibition of p42/p44-MAPK with the chemical inhibitor PD98059, and activation of AKT/P70S6K and p38-MAPK with insulin, produced growth arrest (precluding the expression of PCNA, cyclin-D1 and retinoblastoma at the hyperphosphorylated state and inducing the expression of the cell cycle inhibitor p21 Cip ) and myogenesis (multinucleated myotubes formation and induction of creatine kinase, caveolin-3 and a-actin). Both events were accompanied by down-regulation of AP-1 and up-regulation of NF-kB transcriptional activities. Furthermore, inhibition of NFkB transcriptional activity by the use of the proteasome inhibitor MG132 totally precluded di erentiation by insulin+PD98059, demonstrating a direct role for NFkB on C2Ras myogenesis. C2Ras myoblasts failed to restore di erentiation when rapamycin or PD169316 were added in the presence of insulin+PD98059, indicating that the activation of both P70S6K and p38-MAPK was necessary to reach a fully di erentiated phenotype. Finally, transient transfection of a constitutively active Myr-EGFP-AKT-HA construct (in the presence of PD98059) restored C2Ras myogenesis by its ability to activate P70S6K and p38-MAPK. A crosstalk between P70S6K and p38-MAPK was observed under rapamycin treatment in both insulin or active AKT induced myogenesis. Our results are delineating an AKT/ P70S6K/p38-MAPK pathway involved in skeletal muscle di erentiation.

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Section: Discussionsupporting

confidence: 66%

Section: Ras-transformed C2c12 Myoblasts Fail To Differentiate In Lowmentioning

confidence: 96%

Insulin restores differentiation of Ras-transformed C2C12 myoblasts by inducing NF-κB through an AKT/P70S6K/p38-MAPK pathway

et al. 2002

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“…Bertrand et al (30,31) provided the first evidence of the antiapoptotic function of insulin. These investigators postulate that this antiapoptotic action involves the activation by insulin of nuclear factor κB, a transcription factor playing a critical role in apoptosis inhibition.…”

Section: Discussionmentioning

confidence: 99%

Insulin impairs the maturation of chondrocytes in vitro

Torres

Andrade

Fonseca

et al. 2003

Braz J Med Biol Res

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The precise nature of hormones and growth factors directly responsible for cartilage maturation is still largely unclear. Since longitudinal bone growth occurs through endochondral bone formation, excess or deficiency of most hormones and growth factors strongly influences final adult height. The structure and composition of the cartilaginous extracellular matrix have a critical role in regulating the behavior of growth plate chondrocytes. Therefore, the maintenance of the threedimensional cell-matrix interaction is necessary to study the influence of individual signaling molecules on chondrogenesis, cartilage maturation and calcification. To investigate the effects of insulin on both proliferation and induction of hypertrophy in chondrocytes in vitro we used high-density micromass cultures of chick embryonic limb mesenchymal cells. Culture medium was supplemented with 1% FCS + 60 ng/ml (0.01 µM) insulin and cultures were harvested at regular time points for later analysis. Proliferating cell nuclear antigen immunoreactivity was widely detected in insulin-treated cultures and persisted until day 21 and [ 3 H]-thymidine uptake was highest on day 14. While apoptosis increased in control cultures as a function of culture time, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-labeled cells were markedly reduced in the presence of insulin. Type II collagen production, alkaline phosphatase activity and cell size were also lower in insulin-treated cultures. Our results indicate that under the influence of 60 ng/ml insulin, chick chondrocytes maintain their proliferative potential but do not become hypertrophic, suggesting that insulin can affect the regulation of chondrocyte maturation and hypertrophy, possibly through an antiapoptotic effect.

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“…Also, the altered SOD expression in HeLa cells after low dose gamma-irradiation is responsible for NF-κB-mediated cisplatin resistance (Eichholtz-Wirth et al, 2000). Insulin manifests its antiapoptotic signaling though the activation of NF-κB-dependent survival genes that encode TRAF-2 and SOD (Bertrand et al, 1999). The TNF-inducible zinc finger protein A20 (Opipari et al, 1992) is regulated by NF-κB (Krikos et al, 1992), and the role of this protein in the induction of resistance to TNF-induced apoptosis has been demonstrated (Opipari et al, 1992).…”

Section: How Nf-κb Suppresses Apoptosismentioning

confidence: 99%

Nuclear Factor-κB Activation: A Question of Life or Death

Shishodia¹,

Aggarwal²

2002

BMB Reports

206

168

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Apoptosis is a mode of cell death that plays an important role in both pathological and physiological processes. Research during the last decade has delineated the entire machinery needed for cell death, and its constituents were found to pre-exist in cells. The apoptotic cascade is triggered when cells are exposed to an apoptotic stimulus. It has been known for several years that inhibitors of protein synthesis can potentiate apoptosis that is induced by cytokines and other inducers. Until 1996, it was not understood why protein synthesis inhibitors potentiate apoptosis. Then three reports appeared that suggested the role of the transcription factor NF-κB activation in protecting the cells from TNF-induced apoptosis. Since then several proteins have been identified that are regulated by NF-κB and are involved in cell survival, proliferation, and protection from apoptosis. It now seems that when a cell is attacked by an apoptotic stimulus, the cell responds first by activating anti-apoptotic mechanisms, which may or may not be followed by apoptosis. Whether or not a cell undergoes proliferation, the survival, or apoptosis, appears to involve a balance between the two mechanisms. Inhibitors of protein synthesis seem to suppress the appearance of protein that are involved in anti-apoptosis. The present review discusses how NF-κB controls apoptosis.

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Insulin Antiapoptotic Signaling Involves Insulin Activation of the Nuclear Factor κB-dependent Survival Genes Encoding Tumor Necrosis Factor Receptor-associated Factor 2 and Manganese-superoxide Dismutase

Cited by 49 publications

References 36 publications

Insulin restores differentiation of Ras-transformed C2C12 myoblasts by inducing NF-κB through an AKT/P70S6K/p38-MAPK pathway

Insulin restores differentiation of Ras-transformed C2C12 myoblasts by inducing NF-κB through an AKT/P70S6K/p38-MAPK pathway

Insulin impairs the maturation of chondrocytes in vitro

Nuclear Factor-κB Activation: A Question of Life or Death

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