Weber M J, Nakamura K D, Martinez R
Prog Clin Biol Res. 1983;115:201-16.
The mechanism by which Rous sarcoma virus transforms cells is better understood at the molecular level than that of any other oncogenic agent. The gene (src) responsible for transformation has been identified and its nucleotide sequence has been determined. The transforming protein (pp60src) has been identified and an enzymatic activity assigned to it. The unusual enzymatic activity of pp60src (phosphorylation of proteins on tyrosine) has allowed us to identify a large number of putative targets of this protein. And genetic evidence indicates that the phosphorylation of various targets is responsible for generating the various manifestations of the transformed phenotype. What can this model system contribute to understanding of hereditary large bowel cancer? First of all, it provides an intellectual paradigm for analyzing the mechanism by which a single autosomal dominant gene can alter the metabolism and regulatory behavior of a cell. A cellular homolog of src or of some other onc gene could be responsible for hereditary colon cancer. Second, it provides a model for understanding why some "markers" of malignancy are not invariably associated with cancer: since the oncogenic protein can interact with a variety of primary targets giving rise to the various parameters of transformation, not every sort of biological effect need be necessary for malignancy. Third, it points out that the various syndromes which constitute hereditary colon cancer may well be due to a single gene: since mutations in the src gene are capable of generating a variety of distinct phenotypic alterations in infected cells, different from that generated by the wild-type virus, it certainly is conceivable that different alleles of a single transforming gene could give rise to the different types of hereditary colon cancer. Whether this is the explanation for the various forms of hereditary colon cancer, or whether they result from the activities of several different onc genes can only be determined by identification of the gene(s) at the molecular level. Finally, this model system has provided information which may prove useful in improving the specificity of cancer chemotherapy. Since production of plasminogen activator seems to correlate well with growth in soft agar and tumorigenicity, an anti-cancer prodrug which is activated specifically by cells producing plasminogen activator might be selectively toxic to malignant cells. We have in fact synthesized such drugs and shown them to be selectively toxic in vitro to malignant cells (Carl et al 1980). In vivo tests of these agents are in progress.
与任何其他致癌因子相比，我们在分子水平上对劳氏肉瘤病毒转化细胞的机制有更深入的了解。已鉴定出负责转化的基因（src）并确定了其核苷酸序列。已鉴定出转化蛋白（pp60src）并赋予其一种酶活性。pp60src不寻常的酶活性（蛋白质酪氨酸磷酸化）使我们能够鉴定出该蛋白的大量假定靶点。遗传学证据表明，各种靶点的磷酸化导致了转化表型的各种表现。这个模型系统对理解遗传性大肠癌有什么贡献呢？首先，它为分析单个常染色体显性基因改变细胞代谢和调节行为的机制提供了一个理论范式。src或其他一些癌基因的细胞同源物可能与遗传性结肠癌有关。其次，它为理解为什么某些恶性“标志物”并非总是与癌症相关提供了一个模型：由于致癌蛋白可以与多种主要靶点相互作用，从而产生转化的各种参数，所以并非每种生物学效应对于恶性肿瘤都是必需的。第三，它指出构成遗传性结肠癌的各种综合征很可能是由单个基因引起的：由于src基因的突变能够在受感染细胞中产生多种不同的表型改变，不同于野生型病毒产生的改变，所以完全可以想象单个转化基因的不同等位基因可能导致不同类型的遗传性结肠癌。这是否是各种形式遗传性结肠癌的解释，或者它们是否是由几种不同癌基因的活动导致的，只能通过在分子水平上鉴定基因来确定。最后，这个模型系统提供的信息可能对提高癌症化疗的特异性有用。由于纤溶酶原激活物的产生似乎与软琼脂中的生长和致瘤性密切相关，一种由产生纤溶酶原激活物的细胞特异性激活的抗癌前药可能对恶性细胞具有选择性毒性。事实上，我们已经合成了这样的药物，并证明它们在体外对恶性细胞具有选择性毒性（卡尔等人，1980年）。这些药物的体内试验正在进行中。
