Interaction of Oncogenes with Differentiation Programs

Boettiger, David

doi:10.1007/978-3-642-74697-0_2

Cited by 18 publications

(12 citation statements)

References 293 publications

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“…The results of this study suggest that v-Src blocks myogenic differentiation by targeting the function of MRFs, possibly by acting at the level of their interaction with essential v-Src blocks myogenesis by targeting MyoD and p300 G Falcone et al ubiquitous coregulators that control chromatin remodeling. Given that v-Src interferes with differentiation at a programmatic level (Boettiger, 1989;Thomas and Brugge, 1997), it is proposed that the mechanisms outlined here can be operating in other cell types. Work is in progress to identify the cytoplasmic signaling pathways activated by v-Src that convey the inhibitory signal from the cell periphery to the nucleus eventually leading to block of muscle-specific transcription.…”

Section: P300 Only Rescues Transcription From Extrachromosomal Templatesmentioning

confidence: 99%

“…There are several reasons for utilizing the v-Src tyrosine kinase, a prototypic oncogenic protein, to study the regulation of skeletal muscle differentiation in vitro: (1) v-Src has long been known to exert pleiotropic effects in many different cell types, often resulting in the inhibition of differentiation (Boettiger, 1989;Alema`and Tato`, 1994;Thomas and Brugge, 1997); (2) much information on the role of v-Src downstream effectors such as Ras, Raf and MEK1 in cell transformation is available (Thomas and Brugge, 1997); (3) myoblasts transformed by ts-v-Src exhibit transformation and block of differentiation at the permissive temperature and, upon inactivation of the kinase by shift to the restrictive temperature, fuse into multinucleated myotubes (Falcone et al, 1991), express muscle-specific proteins and assemble highly ordered sarcomeric structures (Castellani et al, 1995(Castellani et al, , 1996. In these cells, where v-Src can be activated at will, it is possible to investigate at the myoblast level the signals promoting the transition to the postmitotic compartment, and at the myotube level the signals underlying the maintenance of the differentiated phenotype (Gallo et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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v-Src inhibits myogenic differentiation by interfering with the regulatory network of muscle-specific transcriptional activators at multiple levels

et al. 2003

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The conversion of skeletal myoblasts to terminally differentiated myocytes is negatively controlled by several growth factors and oncoproteins. In this study, we have investigated the molecular mechanisms by which v-Src, a prototypic tyrosine kinase, perturbs myogenesis in primary avian myoblasts and in established murine C2C12 satellite cells. We determined the expression levels of the cell cycle regulators pRb, cyclin D1 and D3 and cyclindependent kinase inhibitors p21 and p27 in v-Srctransformed myoblasts and found that, in contrast to myogenin, they are normally modulated by differentiative cues, implying that v-Src affects myogenesis independent of cell proliferation. We then examined the levels of expression, DNA-binding ability and transcription-activation potentials of myogenic regulatory factors in transformed myoblasts and in myotubes after reactivation of a temperature-sensitive allele of v-Src. Our results reveal two distinct potential modes of repression targeted to myogenic factors. On the one hand, we show that v-Src reversibly inhibits the expression of MyoD and myogenin in C2C12 cells and of myogenin in quail myoblasts. Remarkably, these loci become resistant to activation of the kinase in the postmitotic compartment. On the other hand, we demonstrate that v-Src efficiently inhibits muscle gene expression by repressing the transcriptional activity of myogenic factors without affecting MyoD DNAbinding activity. Indeed, forced expression of MyoD and myogenin allows terminal differentiation of transformed myoblasts. Finally, we found that ectopic expression of the coactivator p300 restores transcription from extrachromosomal muscle-specific promoters.

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Section: P300 Only Rescues Transcription From Extrachromosomal Templatesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

v-Src inhibits myogenic differentiation by interfering with the regulatory network of muscle-specific transcriptional activators at multiple levels

et al. 2003

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“…It is often surmized that telomerase reactivation is a late event in the multistep process of tumorigenesis and experimental evidence for this hypothesis has been obtained in rodent models of tumor progression (Blasco et al, 1996). Avian unestablished cells can be readily transformed in vitro by a single oncogene (reviewed in AlemaÁ and TatoÁ , 1987;Boettiger, 1989) and, in this respect, they represent a simpli®ed system in which to study carcinogenesis, in comparison to mammalian cells in which transformation and tumorigenicity require the collaborative interaction of more than one oncogene (Weinberg, 1989;Hunter, 1991). Moreover, retroviral infection of primary avian cells allows the introduction of oncogenes with high e ciency, so that the majority of infected cells express the transforming gene within a few population doublings.…”

mentioning

confidence: 99%

Induction of telomerase activity in v-myc-transformed avian cells

Falchetti¹,

Falcone²,

D’Ambrosio³

et al. 1999

Oncogene

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Telomerase activity is detectable in the majority of tumors or immortalized cell lines, but is repressed in most normal human somatic cells. It is generally assumed that reactivation of telomerase prevents the erosion of chromosome ends which occurs in cycling cells and, hence, hinders cellular replicative senescence. Here, we show that the expression of v-Myc oncoprotein by retroviral infection of telomerase-negative embryonal quail myoblasts and chicken neuroretina cells is su cient for reactivating telomerase activity, earlier than telomere shortening could occur. Furthermore, the use of a conditional v-Myc-estrogen receptor protein (v-MycER) causes estrogen-dependent expression of detectable levels of telomerase activity in recently infected chick embryo ®broblasts and neuroretina cells. We conclude that the high levels of telomerase activity in v-Myc-expressing avian cells are not the mere consequence of transformation or of a di erentiative block, since v-Src tyrosine kinase, which prevents terminal di erentiation and promotes cell transformation, fails to induce telomerase activity.

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“…Tumorigenesis involves perturbation of multiple signal transduction cascades resulting in a profound disturbance of normal control of cell cycling, cell growth, and/or cell death (1)(2)(3). Whereas mutated oncogenes and tumor suppres-sor genes play a pivotal role in these processes (4)(5)(6)(7)(8)(9), adapters of signal transduction pathways can also be tumorigenic (10)(11)(12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%