title: Functional dissection of transformation by c-Src and v-Src.
abstract: The c-src proto-oncogene product, c-Src, is frequently over-expressed and activated in various human malignant cancers, implicating a role for c-Src in cancer progression. To verify the role of c-Src, we analyzed the transforming ability of c-Src in mouse embryonic fibroblasts that lack Csk, a negative regulator of Src family kinases. Although Csk deficiency is not sufficient for cell transformation, c-Src over-expression induced characteristic transformed phenotypes including anchorage-independent growth and tumorigenecity. These phenotypes were dose-dependently inhibited by the re-expression of Csk, indicating that there is a certain threshold for c-Src transformation, which is determined by the c-Src : Csk ratio. In contrast to v-Src, c-Src induced the phosphorylation of a limited number of cellular proteins and elicited a restricted change in gene expression profiles. The activation of some critical targets for v-Src transformation, such as STAT3, was not significantly induced by c-Src transformation. Several genes that are involved in cancer progression, that is, cyclin D1 and HIF-1alpha, were induced by v-Src, but not by c-Src. Furthermore, v-Src tumors exhibited aggressive growth and extensive angiogenesis, while c-Src tumors grew more slowly accompanied by the induction of hematomas. These findings demonstrate that c-Src has the potential to induce cell transformation, but it requires coordination with an additional pathway(s) to promote tumor progression in vivo.
authors.affiliation: Department of Oncogene Research, Research Institute of Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Chitose
authors.initials: C
authors.lastname: Oneyama
authors.forename: Tomoya
authors.initials: T
authors.lastname: Hikita
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Nada
authors.forename: Masato
authors.initials: M
authors.lastname: Okada
mesh_terms: D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D019938:Cyclin D1 / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D005786:Gene Expression Regulation; D006406:Hematoma / Q000378:metabolism / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D020411:Oligonucleotide Array Sequence Analysis; D015688:Oncogene Protein pp60(v-src) / Q000502:physiology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D000090063:Proto-Oncogene Mas; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D019061:src-Family Kinases
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D050796:STAT3 Transcription Factor; D019938:Cyclin D1; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D015688:Oncogene Protein pp60(v-src); D019061:src-Family Kinases; C000631346:CSK protein, human