An activated c-Ha-ras allele blocks the induction of muscle-specific genes whose expression is contingent on mitogen withdrawal.

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

doi:10.1073/pnas.84.24.8956

Cited by 63 publications

(65 citation statements)

References 45 publications

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“…Blocking essentially all autocrine growth loops with suramin, a general growth factor antagonist, however, inhibited both proliferation and restored the myogenic phenotype (Giovanni et al, 1995). The ®nding that the degree of proliferation is not inversely proportional to the degree of di erentiation is not surprising since it is well documented that the inhibition of di erentiation by growth factors or by oncogenic Ras is independent of their mitogenicity Olson et al, 1987;Payne et al, 1987;Gossett et al, 1988;Lathrop et al, 1985;Rosenthal and Cheng, 1995;Weyman et al, 1997). It is somewhat intriguing, however, that blocking both FGF-2 and IGF does not revert the di erentiation-defective phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, while treatment of 23A2 myoblasts with either FGF-2 or IGF-1 inducs a slight increase in the incorporation of thymidine into newly synthesized DNA, treatment of 23A2 myoblasts with A2:H-Ras conditioned DM does not (d.n.s.). The ®nding that A2:HRas conditioned DM blocks 23A2 myoblast differentiation without inducing proliferation is not surprising since it is well documented that the inhibition of di erentiation by growth factors or by oncogenic Ras does not rely on their mitogenic potential Olson et al, 1987;Payne et al, 1987;Gossett et al, 1988;Lathrop et al, 1985;Rosenthal and Cheng, 1995;Weyman et al, 1997).…”

Section: A2:h-ras Conditioned Media Does Not Mimic the Actions Of Fgfmentioning

confidence: 99%

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Oncogenic Ras-induced secretion of a novel inhibitor of skeletal myoblast differentiation

Weyman

Wolfman

1997

Oncogene

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Expression of oncogenic H-Ras in 23A2 myoblasts (A2:H-Ras cells) is su cient to induce both a transformed phenotype and a di erentiation-defective phenotype. Because oncogenic Ras is known to induce the secretion of several di erent growth factors involved in maintaining the transformed phenotype of both ®broblast and epithelial cells, we explored the possibility that expression of oncogenic Ras in 23A2 myoblasts might lead to the secretion of a factor which inhibits di erentiation. The di erentiation of 23A2 myoblasts was inhibited (i) by coculture with an equal number of A2:H-Ras cells, (ii) by culture with an equal number of A2:H-Ras cells in the same tissue culture medium on an insert which allowed equilibration of molecules smaller than 1 micron, and (iii) by culture in media previously conditioned by A2:H-Ras cells. Similar results were obtained when 23A2 myoblasts expressing oncogenic NRas were substituted for A2:H-Ras cells in each assay. No inhibition of di erentiation was observed, however, when di erentiation-defective E1A-expressing 23A2 cells or C3H10T1/2 ®broblasts were substituted for A2:HRas cells. The di erentiation inhibitor(s) in media conditioned by A2:H-Ras cells is heat stable, larger than 3 kD, and sensitive to the non-speci®c growth factor antagonist, suramin. Western analyses failed to detect either FGF-2 or TGFb (the known inhibitors of myoblast di erentiation) in media conditioned by A2:H-Ras cells. Furthermore, while FGF-2 is a potent activator of MAP kinase and TGFb is a potent inhibitor of mink lung epithelial cell (CCL64) growth, conditioned media from A2:H-Ras cells does not activate MAP kinase and does not inhibit the growth of CCL64 cells. These results indicate that expression of oncogenic Ras induces the secretion of a novel inhibitor of skeletal myoblast di erentiation. Furthermore, these results are the ®rst to implicate an autocrine/paracrine mechanism in the inhibition of di erentiation by oncogenic Ras.

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Section: Discussionmentioning

confidence: 99%

Section: A2:h-ras Conditioned Media Does Not Mimic the Actions Of Fgfmentioning

confidence: 99%

Oncogenic Ras-induced secretion of a novel inhibitor of skeletal myoblast differentiation

Weyman

Wolfman

1997

Oncogene

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“…Previous reports have shown that most Ras-family GTP-binding proteins, such as H-Ras, N-Ras, Rap1 and TC21, inhibit skeletal muscle dierentiation Payne et al, 1987;Konieczny et al, 1989;Lassar et al, 1989;Pizon et al, 1999;Graham et al, 1999). The Ras-regulated signaling pathways leading to the inhibition of myogenesis are being clari®ed.…”

Section: Discussionmentioning

confidence: 99%

“…The dierentiation is also inhibited by expression of several oncogenes such as myc, fos, jun and ras (Olson, 1992). It is well-established that oncogenic Ras inhibits skeletal myogenesis, probably through mimicking signaling events exerted by growth factors Payne et al, 1987;Konieczny et al, 1989;Lassar et al, 1989). In addition to Ras, two other Ras-family proteins, Rap1 and TC21, also block skeletal myogenesis (Pizon et al, 1999;Graham et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Positive regulation of skeletal myogenesis by R-Ras

2000

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Most of the proteins in the Ras-family proteins, including Ras, Rap and TC21, have been reported to be strong inhibitors of skeletal myogenesis. Here we show that R-Ras, another member of this family, promotes terminal dierentiation of C2C12 skeletal myoblasts. In contrast to Ras, which induced a markedly transformed phenotype of C2C12 cells, an activated mutant of R-Ras (R-Ras Q87L ) did not exhibit any inhibitory eect on the dierentiation of C2C12 cells, but enhanced the formation of multinucleated myotubes. Although R-Ras Q87L showed little eect on induction of two muscle-speci®c proteins, creatine kinase and myogenin, it prevented cell death during myoblast dierentiation, probably through Akt activation and Bcl-x L induction. Motility of C2C12 cells, which may be involved in fusion of myoblasts, was also stimulated by R-Ras Q87L. Furthermore, we observed a transient activation of endogenous R-Ras during dierentiation of C2C12 cells. The ectopic expression of R-Ras GAP inhibited the dierentiation. These results suggest that R-Ras has a positive eect on the terminal dierentiation of myoblasts and may be involved in the program of skeletal myogenesis.

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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, ...

show abstract

An activated c-Ha-ras allele blocks the induction of muscle-specific genes whose expression is contingent on mitogen withdrawal.

Cited by 63 publications

References 45 publications

Oncogenic Ras-induced secretion of a novel inhibitor of skeletal myoblast differentiation

Oncogenic Ras-induced secretion of a novel inhibitor of skeletal myoblast differentiation

Positive regulation of skeletal myogenesis by R-Ras

Amplification of MDM2 Inhibits MyoD-Mediated Myogenesis

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