Plasticity of the Differentiated State

Blau, Helen M.; Pavlath, Grace K.; Hardeman, Edna C.; Chiu, Choy‐Pik; Silberstein, L.; Webster, Steven G.; Miller, Shannon C.; Webster, Cecelia

doi:10.1126/science.2414846

Cited by 779 publications

(332 citation statements)

References 97 publications

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“…Myc and Bin1 are each expressed in proliferating C2C12 cells with Bin1 in stochiometric excess (Wechsler-Reya et al, 1998). When C2C12 is induced to di erentiate (Blau et al, 1985), Bin1 is upregulated while Myc is downregulated to undetectable levels (Wechsler-Reya et al, 1998), providing a useful negative control for association. As before, Myc was extracted ine ciently by NP40 bu er but Bin1 was detected in Myc complexes that were immunoprecipitated by Myc antibody (Figure 1b).…”

Section: Physical and Functional Association Of Myc And Bin1 In Cellsmentioning

confidence: 99%

Bin1 functionally interacts with Myc and inhibits cell proliferation via multiple mechanisms

et al. 1999

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Section: Physical and Functional Association Of Myc And Bin1 In Cellsmentioning

confidence: 99%

Bin1 functionally interacts with Myc and inhibits cell proliferation via multiple mechanisms

et al. 1999

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“…Mouse C2C12 (C2) myoblasts (American Type Culture Collection) (Blau et al, 1985) were maintained in DMEM supplemented with 10% FS and antibiotics, at 378C and 5% CO 2 . v-H-ras transformed C2C12 myoblasts (C2Ras) were obtained by infection with a retroviral construct containing oncogen v-H-ras (pRNR16) and selected by neomycin resistance in G418 (0.5 mg/ml) for 3 weeks.…”

Section: Cell Culture and Transfectionsmentioning

confidence: 99%

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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“…The mouse myoblast line C2C12 (Blau et al, 1985) was cultured as in Tiainen et al (1996b). Di erentiation was induced by starving the cells in serum-free (SF) medium.…”

Section: Cellsmentioning

confidence: 99%

E2F activates late-G1 events but cannot replace E1A in inducing S phase in terminally differentiated skeletal muscle cells

Pajalunga¹,

Tognozzi²,

Tiainen

et al. 1999

Oncogene

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We have previously shown that the adenovirus E1A oncogene can reactivate the cell cycle in terminally di erentiated cells. Current models imply that much or all of this E1A activity is mediated by the release of the E2F transcription factors from pocket-protein control. In contrast, we show here that overexpression of E2F-1, E2F-2 and E2F-4, or a chimeric E2F-4 tethered to a nuclear localization signal cannot reactivate postmitotic skeletal muscle cells (myotubes). This is not due to lack of transcriptional activity, as demonstrated on both a reporter construct and a number of endogenous target genes. Although cyclin E was strongly overexpressed in E2F-transduced myotubes, it lacked associated kinase activity, possibly explaining the inability of the myotubes to enter S phase and accumulate cyclin A. Although E2F is not su cient to trigger DNA synthesis in myotubes, its activity is necessary even in the presence of E1A, as dominant-negative DP-1 mutants inhibit E1A-mediated cell cycle reentry. Our data show that, to reactivate myotubes, E1A must exert other functions, in addition to releasing E2F. They also establish mouse myotubes as an experimental system uniquely suited to study the most direct E2F functions in the absence of downstream cell cycle e ects.

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Plasticity of the Differentiated State

Cited by 779 publications

References 97 publications

Bin1 functionally interacts with Myc and inhibits cell proliferation via multiple mechanisms

Bin1 functionally interacts with Myc and inhibits cell proliferation via multiple mechanisms

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

E2F activates late-G1 events but cannot replace E1A in inducing S phase in terminally differentiated skeletal muscle cells

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