Autonomous expression of c-myc in BC3H1 cells partially inhibits but does not prevent myogenic differentiation.

Schneider, Michael; Perryman, M. Benjamin; Payne, P. A.; Spizz, Gwendolyn; Roberts, Robert; Olson, Eric N.

doi:10.1128/mcb.7.5.1973

Cited by 82 publications

(57 citation statements)

References 41 publications

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“…In addition to promoting tumor formation, anchorage-independent growth, and cellular immortalization, expression of transforming oncogenes inhibits cellular differentiation in several different cell lineages. In muscle cells, expression of oncogenic tyrosine kinases (v-src and v-fps), growth factor receptors (v-erbB), nuclear oncogene products (v-myc, c-myc, v-erbA, and E1A), and the activated forms of signal-transducing G proteins (H-ras and N-ras) can inhibit terminal differentiation to various extents (5,7,10,14,30,31,37,45). We previously demonstrated that ras and fos prevent myogenesis by inhibiting expression of MyoD (19).…”

Section: Discussionmentioning

confidence: 99%

Amplification of MDM2 Inhibits MyoD-Mediated Myogenesis

Fiddler

Smith

Tapscott

et al. 1996

Molecular and Cellular Biology

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One obvious phenotype of tumor cells is the lack of terminal differentiation. We previously classified rhabdomyosarcoma cell lines as having either a recessive or a dominant nondifferentiating phenotype. To study the genetic basis of the dominant nondifferentiating phenotype, we utilized microcell fusion to transfer chromosomes from rhabdomyosarcoma cells into C2C12 myoblasts. Transfer of a derivative chromosome 14 inhibits differentiation. The derivative chromosome 14 contains a DNA amplification. MDM2 is amplified and overexpressed in these nondifferentiating hybrids and in the parental rhabdomyosarcoma. Forced expression of MDM2 inhibits MyoD-dependent transcription. Expression of antisense MDM2 restores MyoD-dependent transcriptional activity. We conclude that amplification and overexpression of MDM2 inhibit MyoD function, resulting in a dominant nondifferentiating phenotype.Rhabdomyosarcomas are one of the most common solid tumors of childhood. Sarcomas have traditionally been classified as rhabdomyosarcomas on the basis of morphology and the expression of muscle structural genes, such as that for the myosin heavy chain (MHC) or desmin. Expression of MyoD has been shown to be the most sensitive marker for classifying sarcomas as rhabdomyosarcomas (4, 38). Rhabdomyosarcomas are grouped by histologic and cytogenetic criteria as either embryonal or alveolar rhabdomyosarcomas: a balanced translocation between chromosomes 2 and 13, t(2;13)(q35;q14), is associated with alveolar rhabdomyosarcomas (1). The PAX3 gene has been shown to be fused to a member of the forkhead gene family in the t(2;13) translocation (1, 39). Loss of heterozygosity on the short arm of chromosome 11 encompassing 11p15.5 is associated not only with embryonal rhabdomyosarcomas (38) but also with a number of other solid tumors (26), suggesting the location of a tumor suppressor gene(s) for multiple tumor types in this region.Recently, we have begun an analysis of five rhabdomyosarcoma cell lines (RD, Rh18, Rh28, Rh30, and RhJT) for expression and function of the MyoD family (42). We showed that even though MyoD is expressed in rhabdomyosarcoma cells, it is nonfunctional in inducing differentiation. Heterokaryon formation between 10T1/2 cells and RD, Rh28, Rh30, and RhJT cells results in differentiation of the heterokaryons into muscle and restoration of transcriptional activation by MyoD, indicating that these tumor lines display a recessive nondifferentiating phenotype. In contrast, heterokaryon formation with the rhabdomyosarcoma Rh18 and 10T1/2 cells did not result in myogenesis, suggesting that Rh18 cells display a dominant nondifferentiating phenotype.In this paper, we show that transfer of a derivative chromosome 14 from Rh18 cells into the differentiation-competent myoblast cell line C2C12 inhibits muscle differentiation and the ability of MyoD to function as a transcription factor. The derivative chromosome 14 contains a region of amplified DNA originating from chromosome 12 and contains a number of genes often amplified in sarcomas, ...

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Section: Discussionmentioning

confidence: 99%

Amplification of MDM2 Inhibits MyoD-Mediated Myogenesis

Fiddler

Smith

Tapscott

et al. 1996

Molecular and Cellular Biology

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“…A similar effect has been observed in myoblasts constitutively expressing v-jun mRNA, as myotubes that form in these cells have lost Jun nuclear staining (Grossi et al 1991;Su et al 1991). Also, as constitutive expression of c-myc mRNA has been shown to block myogenesis to varying extents under different experimental conditions (Schneider et al 1987;Miner and Wold 1991), it will be of interest to see whether levels of Myc protein in the nuclei of these cells determine the differentiated state of the cell.…”

Section: Genes and Developmentmentioning

confidence: 99%

Overexpression of Id protein inhibits the muscle differentiation program: in vivo association of Id with E2A proteins.

Jen¹,

Weintraub²,

Benezra³

1992

Genes Dev.

449

364

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The helix-loop-helix (HLH) protein Id lacks the basic DNA-binding domain common to this class of proteins. In vitro experiments suggested that Id could associate tightly with two other HLH proteins encoded by the E2A gene, El2 and E47 (referred to here collectively as E proteins) and prevent their binding to a sequence present in the muscle creatine kinase (MCK) enhancer either as homo-oligomers or hetero-oligomers with MyoD. In this report we present evidence for the in vivo roles of Id and E proteins: (1) Id and E proteins cofractionate and coimmunoprecipitate in whole-cell extracts prepared from myoblasts; (2) the loss of Id protein observed during the conversion of proliferating myoblasts into mature myotubes correlates with the formation of MyoD/E hetero-oligomeric complexes in whole-cell extracts (these complexes do not form when purified Id protein is added to the extracts); and (3) stable overexpression of Id mRNA and protein in the C2C12 muscle cell line inhibits differentiation in these cells 16 hr postinduction. The myotubes that do eventually form 48 hr postinduction have no detectable Id protein in the nucleus despite the persistence of exogenous Id mRNA. These data support a model in which Id can inhibit muscle cell differentiation by associating with E proteins and preventing them from forming active hetero-oligomeric complexes with the muscle determination gene products.

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“…Recent evidence indicates that cyclins are downstream targets of c-Myc in cell cycle activation (Jansen-DuÈ rr et al, 1993;Hoang et al, 1994;Philipp et al, 1994;Rudolph et al, 1996). Ectopic expression of c-myc inhibits terminal dierentiation in a variety of cell lines including mouse erythroleukemia (MEL) cells (Coppola and Cole, 1986;Prochownik and Kukowska, 1986), F9 teratocarcinoma cells (Griep and Westphal 1988), monoblastic U-937 cells (Larsson et al, 1988), and myoblasts (Schneider et al, 1987;Miner and Wold, 1991). Overexpression of c-myc has been shown to inhibit dierentiation of 3T3-L1 cells possibly by precluding the entry of cells into a distinct predifferentiation stage in G0/G1 (Freytag, 1988).…”

Section: Introductionmentioning

confidence: 99%

Analysis of cell cycle arrest in adipocyte differentiation

Reichert¹,

Eick²

1999

Oncogene

112

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Con¯uent 3T3-L1 preadipocytes dierentiate to adipocytes in the presence of insulin, dexamethasone, and isobutylmethylxanthine (IDI). A transient increase of DNA synthesis is induced in 3T3-L1 cells 18 h after addition of IDI, followed by an arrest in the G1 phase of the cell cycle. Growth arrested cells express the protooncogene c-myc and the gene for the CCAAT/enhancer binding protein (C/EBPa) between day 2 and 5. While cMyc is strongly implicated in cell proliferation, C/EBPa is a dierentiation-speci®c transcription factor with antiproliferative activity. Here we have characterized the cell cycle arrest in dierentiating 3T3-L1 cells. Arrested cells express the Cdk inhibitors p21 and p27, but, at the same time, show hyperphosphorylation of Rb and expression of the E2F-regulated thymidine kinase gene. The addition of new serum to arrested cells resulted in cyclin A expression and Cdk2 activity, but not in DNA synthesis. Simian virus 40 large tumor antigen (LTAg) is a potent mitogen. The mutant LTAg-K1, de®cient in binding of pocket proteins and unable to induce DNA synthesis in serum-starved 3T3-L1 cells, eciently induced DNA synthesis in dierentiating 3T3-L1 cells. This indicates that pocket proteins are probably not involved in the control of the cell cycle arrest during 3T3-L1 cell dierentiation. Our data suggest that the dierentiationspeci®c cell cycle block in 3T3-L1 cells is resistant to high levels of c-Myc, inactivation of pocket proteins, upregulation of cyclin A levels, and Cdk2 activation, but can be abolished by a function of LTAg that is independent of binding to pocket proteins.

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Autonomous expression of c-myc in BC3H1 cells partially inhibits but does not prevent myogenic differentiation.

Cited by 82 publications

References 41 publications

Amplification of MDM2 Inhibits MyoD-Mediated Myogenesis

Amplification of MDM2 Inhibits MyoD-Mediated Myogenesis

Overexpression of Id protein inhibits the muscle differentiation program: in vivo association of Id with E2A proteins.

Analysis of cell cycle arrest in adipocyte differentiation

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