Stable expression of intracellular Notch suppresses v-Src-induced transformation in avian neural cells.
Understanding how disruption of differentiation contributes to the cancer cell phenotype is required to identify alterations essential for malignant transformation and provide experimental basis for their correction. We investigated whether primary quail neuroretina cells, transformed by a conditional v-Src mutant (QNR/v-src(ts)), could revert to a normal phenotype, in response to the stable expression of constitutively active Notch1 intracellular domain (ICN). This model system was chosen because Notch signaling plays an instructive role in cell fate determination during NR development, and because the intrinsic capacity of QNR cultures to differentiate is blocked by v-Src. We report that stable ICN expression results in suppression of QNR/v-src(ts) cell transformation in the presence of an active oncoprotein. This phenotypic reversion coincides with a major switch in cell identity, as these undifferentiated cells acquire glial differentiation traits. Both changes appear to be mediated by CBF, a transcription factor that binds to ICN and activates target genes. Cells restored to a normal and differentiated phenotype have undergone changes in the functioning of signaling effectors, essentially regulating cell morphology and cytoskeleton organization. This dominant interference may be partially mediated by an autocrine/paracrine mechanism, as revertant cells secrete a factor(s), which inhibits transformation properties of QNR/v-src(ts) cells.
Mateos
S
S
UMR 146 du CNRS-Institut CURIE, Centre Universitaire, Orsay Cedex, France.
Amarir
S
S
Laugier
D
D
Marx
M
M
Calothy
G
G
D000818:Animals; D015415:Biomarkers; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D015536:Down-Regulation; D015870:Gene Expression; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D015688:Oncogene Protein pp60(v-src) / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011784:Quail; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D054462:p21-Activated Kinases; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D015415:Biomarkers; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D051881:Receptor, Notch1; D015688:Oncogene Protein pp60(v-src); D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020741:rho GTP-Binding Proteins