Functional dissection of transformation by c-Src and v-Src
Functional dissection of transformation by c-Src and v-Src
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DOI：
10.1111/j.1365-2443.2007.01145.x
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发表时间：
2008-01-01
期刊：
影响因子：
2.1
通讯作者：
Okada, Masato
中科院分区：
文献类型：
--
作者：
Oneyama, Chitose;Hikita, Tomoya;Okada, Masato
c-src原癌基因产物c-Src在各种人类恶性肿瘤中经常过度表达和活化，暗示c-Src在癌症进展中的作用。为了验证c-Src的作用，我们分析了c-Src在缺乏Csk（Src家族激酶的负调节因子）的小鼠胚胎成纤维细胞中的转化能力。虽然Csk缺陷不足以导致细胞转化，但c-Src过表达诱导了特征性转化表型，包括锚定非依赖性生长和致瘤性。这些表型被Csk的再表达剂量依赖性地抑制，表明c-Src转化存在一定的阈值，其由c-Src：Csk比率确定。与v-Src相反，c-Src诱导了有限数量的细胞蛋白的磷酸化，并引起了基因表达谱的有限变化。v-Src转化的一些关键靶点如STAT 3的激活并不被c-Src转化显著诱导。参与癌症进展的几个基因，即细胞周期蛋白D1和HIF-1 α，被v-Src诱导，但不被c-Src诱导。此外，v-Src肿瘤表现出积极的增长和广泛的血管生成，而c-Src肿瘤生长缓慢，伴随着血肿的诱导。这些发现表明c-Src具有诱导细胞转化的潜力，但它需要与其他途径协调以促进体内肿瘤进展。
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-1 alpha, 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.