Temperature-sensitive expression of differentiation in transformed myoblasts

The question whether some events which control differentiation can modulate the course of viral-induced transformation is an important one and the answer to this question may throw some light on the mechanism of transformation as well as differentiation. There are several reports that cells in muscle cultures can be infected with either DNA or RNA viruses (1-6). However, muscle cultures, and even "muscle clones" consist of a heterogeneous population of cells in different compartments of the myogenic and fibrogenic lineages, and it is by no means clear whether these different phenotypes respond to the viruses in the same manner (7). For example, when muscle cultures are treated with oncogenic virus, does the virus transform both replicating myogenic and post-mitotic myogenic cells? Will the post-mitotic nuclei in infected myotubes integrate the virus, transcribe the viral genome, and transform? Will normal, post-mitotic myotube nuclei be induced to reenter the cell cycle and undergo mitosis as claimed by some investigators (3, 6)? Clearly, answers to these questions will contribute to understanding myogenesis, and could provide a useful model for following events responsible for transformation.We have confirmed previous observations on the effect of wild-type Rous sarcoma virus (RSV) on muscle cultures (5). Replicating myogenic cells exposed to RSV fused to form post-mitotic, multinucleated myotubes, but these myotubes invariably vacuolated and degenerated within the next

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“…What these investigators interpreted as DNA synthesis and metaphase chromosomes, others (13,23) (31,32).…”

Section: Discussionmentioning

confidence: 99%

Effect of oncogenic virus on muscle differentiation.

Holtzer¹,

Biehl²,

Yeoh³

et al. 1975

Proc. Natl. Acad. Sci. U.S.A.

141

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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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“…Expression of the viral src gene is responsible for the initiation and maintenance of transformation of cultured cells and for the production of tumors in vivo, the latter exhibiting a target specificity for cells of mesodermal origin (2,11,14,19,30). Expression of the viral gene product pp60v-rc has also been shown to interfere with the differentiation of cultured chick myoblasts, melanoblasts, and chondroblasts (3,8,21) and to elicit a cell-specific response in the three layers of the embryonic chorioallantoic membrane (7). This evidence led us to examine developing chicken embryos for tissue-specific differences in the expression of c-src in an attempt to understand the function of the cellular src protein.…”

mentioning

confidence: 99%

Neural tissues express high levels of the cellular src gene product pp60c-src.

Cotton¹,

Brugge²

1983

Mol. Cell. Biol.

295

139

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Chicken embryo tissues were examined for the expression of pp60c-src, the normal cellular homolog of the transforming protein of Rous sarcoma virus. Three assays, including a solid-phase radioimmunoassay, a competitive radioimmunoprecipitation assay, and an immune complex protein kinase assay, were employed. Elevated levels of pp60c-src were detected in lysates from several neural tissues, including brain, retina, and spinal ganglia. Other tissues contained 8- to 10-fold-lower levels of pp60c-src, levels comparable to those found in chicken embryo fibroblasts. Expression of pp60c-src in brain tissues was also shown to vary with the developmental stage of the embryo.

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Temperature-sensitive expression of differentiation in transformed myoblasts

Cited by 168 publications

References 16 publications

Effect of oncogenic virus on muscle differentiation.

Effect of oncogenic virus on muscle differentiation.

Amplification of MDM2 Inhibits MyoD-Mediated Myogenesis

Neural tissues express high levels of the cellular src gene product pp60c-src.

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