TRANSFORMING DOMAINS IN THE IGF-1 RECEPTOR

我们已经从小鼠胚胎中获得了纯合的细胞系，用于靶向 胰岛素样生长因子1型受体(IGF-1R)的破坏 Gen(Lui等人)1993年，Baker等人提出的。1993年)。这些IGF-1的细胞系 R基因敲除小鼠和野生型窝产仔(分别为R-和W) 它们的增长和转型的相对容易程度是不同的。R细胞， 与W细胞不同的是，在无血清培养中不会发生细胞分裂 补充PDGF、EGF、IGF-1，不能通过 介绍猴病毒40(SV4O)大T抗原。R细胞 表达SV4OT抗原((TSA)R-)保留了 正常成纤维细胞在含血清的培养液中。《重返荒野》 胰岛素样生长因子-1受体进入沙皇细胞后恢复细胞转化能力 SV4OT抗原。初步数据表明，有明显的 由细胞内的IGF-1R产生的信号是专用于 DNA合成或增殖(即进入有丝分裂)，以及这些 信号可能与细胞转化所需的信号分开。一个 截短的IGF-1R允许R细胞增殖以响应IGF-1，但 不允许在(TSA)R细胞中转化。为了扩展这些功能， 结果，并检查细胞信号在 我们建议在受体中引入特定的突变，并 在R-和(TSA)R-细胞中表达这些突变受体。的能力 这些突变的受体诱导进入S期，有丝分裂和各种 转变的方面；即焦点形成、锚定独立 生长和致瘤性将被决定。

We have derived cell lines from mouse embryos homozygous for a targeted disruption of the insulin like growth factor type 1 receptor (IGF-1 R) gene (Lui et al. 1993, Baker et al. 1993). The cell lines from these IGF-1 R knockout mice and from wild type littermates (R- and W respectively) differ in their growth and relative ease of transformation. The R- cells, unlike W cells, do not undergo cell division in serum free medium supplemented with PDGF, EGF, IGF-1, and cannot be transformed by the introduction of the simian virus 40 (SV4O) large T antigen. The R- cells expressing the SV4O T antigen ((tsA)R-) retain the characteristics of normal fibroblasts in serum containing medium. Reintroduction of the wild type IGF-1 R into the tsAR- cells restores the transforming capacity of the SV4O T antigen. Preliminary data indicates that there are distinct signals generated by the IGF-1 R within the cell which are specific for DNA synthesis or proliferation (i.e. entry into mitosis) and that these signals may be separate from those needed for cellular transformation. A truncated IGF-1 R allows R-cells to proliferate in response to IGF-1 but does not allow transformation in (tsA)R- cells. In order to extend these results and to examine divergence of cellular signals at the level of the IGF-1 R we propose to introduce specific mutations in the receptor and to express these mutant receptors in R- and (tsA)R- cells. The ability of these mutant receptors to induce entry into S phase, mitosis and various aspects of transformation; i.e. foci formation, anchorage independent growth, and tumorigenicity, will be determined.