CYTOSKELETAL PROTEINS IN ONCOGENIC TRANSFORMATION AND HUMAN NEOPLASIA

我们一直在继续我们对压抑的关系的研究 原肌球蛋白(TM)合成向肿瘤转化。上一首 观察结果使我们假设：a.)TM抑制是一种 肿瘤性转化中的因果事件；致癌途径 由许多不同的癌基因和其他方式启动 会聚在TM压制上，并通过TM压制采取行动。我们已经获得了证据 通过恢复TM1的表达来支持这一假说 V-Ki-ras基因转化的NIH3T3细胞系DT、 通过使用携带全长cDNA的逆转录病毒载体(PBNC) 编码人类TM1。表达该cdna的细胞克隆的表达水平升高。 TM1，失去了在锚地独立条件下生长的能力 条件。它们也没有参与肿瘤的形成 无性系小鼠。受试者体内TM水平升高的能力 将用于细胞骨架的克隆正在研究中，它们的 TM参与的生理二聚体的形成 在活体内发生。转化表型的完全逆转可能 需要同时恢复TM1和TM2以允许形成 异二聚体TM分子，这是体内的首选形式。 已有克隆中插入TM2编码基因的材料 恢复的TM1表达现在正在准备中。TM1表达式具有 在人类乳腺癌细胞系MCF-7中也得到了恢复，我们 先前显示该TM异构体的合成有缺陷。 这种修复对肿瘤表型的影响的测试是 目前正在进行中。

We have continued our studies on the relationship of suppression of tropomyosin (TM) synthesis to neoplastic transformation. Previous observations have led us to hypothesize that: a.) TM suppression is a causal event in neoplastic transformation; and b.) the oncogenic pathways initiated by a number of different oncogenes and other modalities converge on and act through TM suppression. We have obtained evidence supporting this hypothesis by restoring expression of TM1, one of two suppressed tropomyosins in the v-Ki-ras transformed NIH3T3 cell line, DT, through the use of a retroviral vector (pBNC) carrying a full length cDNA encoding human TM1. Cell clones expressing the cDNA had elevated levels of TM1 and lost the ability to grow under anchorage-independent conditions. They also did not participate in formation of tumors in athymic mice. The ability of elevated levels of TM in the transduced clones to be utilized in the cytoskeleton is under study, as is their participation in the formation of the physiological dimers in which TM occurs in vivo. Complete reversal of the transformed phenotype may require simultaneous restoration of both TM1 and TM2 to permit formation of hereodimeric TM molecules, which are the preferred form in vivo. Materials for the insertion of TM2-encoding cDNA into clones already restored in TM1 expression are now being prepared. TM1 expression has also been restored in the human breast cancer cell line, MCF-7, which we previously showed to be defective in synthesis of this TM isoform. Testing for effects of this restoration on the neoplastic phenotype is currently in progress.