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v-Src inhibits myogenic differentiation by interfering with the regulatory network of muscle-specific transcriptional activators at multiple levels.
Oncogene. 2003 Nov 13; 22(51):8302-15.O

Abstract

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 cyclin-dependent kinase inhibitors p21 and p27 in v-Src-transformed 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 DNA-binding 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.

Authors+Show Affiliations

Istituto di Biologia Cellulare, Consiglio Nazionale delle Ricerche, Monterotondo 00016, Italy. gfalcone@ibc.cnr.itNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

14614454

Citation

Falcone, Germana, et al. "V-Src Inhibits Myogenic Differentiation By Interfering With the Regulatory Network of Muscle-specific Transcriptional Activators at Multiple Levels." Oncogene, vol. 22, no. 51, 2003, pp. 8302-15.
Falcone G, Ciuffini L, Gauzzi MC, et al. V-Src inhibits myogenic differentiation by interfering with the regulatory network of muscle-specific transcriptional activators at multiple levels. Oncogene. 2003;22(51):8302-15.
Falcone, G., Ciuffini, L., Gauzzi, M. C., Provenzano, C., Strano, S., Gallo, R., Castellani, L., & Alemà, S. (2003). V-Src inhibits myogenic differentiation by interfering with the regulatory network of muscle-specific transcriptional activators at multiple levels. Oncogene, 22(51), 8302-15.
Falcone G, et al. V-Src Inhibits Myogenic Differentiation By Interfering With the Regulatory Network of Muscle-specific Transcriptional Activators at Multiple Levels. Oncogene. 2003 Nov 13;22(51):8302-15. PubMed PMID: 14614454.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - v-Src inhibits myogenic differentiation by interfering with the regulatory network of muscle-specific transcriptional activators at multiple levels. AU - Falcone,Germana, AU - Ciuffini,Laura, AU - Gauzzi,Maria-Cristina, AU - Provenzano,Claudia, AU - Strano,Sabrina, AU - Gallo,Rita, AU - Castellani,Loriana, AU - Alemà,Stefano, PY - 2003/11/14/pubmed PY - 2004/1/6/medline PY - 2003/11/14/entrez SP - 8302 EP - 15 JF - Oncogene JO - Oncogene VL - 22 IS - 51 N2 - 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 cyclin-dependent kinase inhibitors p21 and p27 in v-Src-transformed 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 DNA-binding 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. SN - 0950-9232 UR - https://www.unboundmedicine.com/medline/citation/14614454/v_Src_inhibits_myogenic_differentiation_by_interfering_with_the_regulatory_network_of_muscle_specific_transcriptional_activators_at_multiple_levels_ L2 - https://doi.org/10.1038/sj.onc.1206915 DB - PRIME DP - Unbound Medicine ER -