CONVERSION OF EMBRYONIC CELLS INTO TRANSFORMED CELLS

细胞内控制正常细胞的出现， 定形肌肉、软骨或色素细胞可产生肿瘤细胞 自Boveri的时代以来，60多年来一直在讨论它们何时发生故障 前 为此，研究了TPA、EMS、pp 60 v-src和BrUdR对 原代培养的肌源性、软骨源性和 黑色素细胞进行了研究。 这4个多效性分子，每个都有一个 不同的初始细胞内靶点，都有一个显著的特性- 它们选择性地但可逆地阻断转录的亚群， 定义被处理细胞的分化程序的基因。 这些 结论来自以下（a）细胞特异性的合成 蛋白质，和（B）这些细胞特异性mRNA在细胞中的积累。 处理的细胞。 正常细胞分化的脆弱性 对这些药物的程序不能归因于广义的细胞毒性 反应，但可能类似于转录反应， 热休克细胞 细胞分化程序的半自主性 在调节“家庭”分子的背景下是惊人的。 这些实验也为研究 正常的肌原纤维形成和软骨形成，以及 c-癌基因在调节增殖和/或细胞多样化中的作用。 我们对正常细胞多样化和转化的共同模型 假设细胞特异性亚群的谱系依赖性激活 在给定谱系的早期区室中活跃的基因，在 后车厢。 为了测试这一点，将0-16小时的鸡胚盘细胞进行了培养。 分离并低密度培养。 他们证明了几小时前 到原肠胚形成，在假定的“细胞-细胞”之前， 上皮-间充质诱导相互作用”，胚盘细胞已经被 引导到不同的，短暂的，创始人细胞的多，双， 单潜能谱系 这些发现表明，早期和晚期 反映了遗传预编程的细胞内 变化，而不是主要由外源分子引起的变化。 这些结论也与独特的命题相一致， 任何给定类型的转化细胞的表型特性必须是 由其正常祖细胞的分化程序预先确定。

That the intracellular controls which regulate the emergence of a normal definitive muscle, cartilage, or pigment cell may produce neoplastic cells when they malfunction has been discussed since Boveri's time over 60 years ago. To this end, the impact of TPA, EMS, pp60 v-src, and BrUdR on the differentiation programs of primary cultured myogenic, chondrogenic, and melanogenic cells is studied. These 4 pleiotropic molecules, each having a different initial intracellular target, share one remarkable property - they selectively, but reversibly block transcription of that subset of genes which define the treated cell's differentiation program. These conclusions derive from following (a) the synthesis of cell-specific proteins, and (b) the accumulation of these cell-specific mRNAs in the treated cells. The vulnerability of a normal cell's differentiation program to these agents cannot be ascribed to a generalized cytotoxicity reaction, but may be analogous to the transcriptional response of heat-shocked cells. The semi-autonomy of a cell's differentiation program in the context of the regulation of "household" molecules is striking. These experiments also provide unusually favorable models for the study of normal myofibrillogenesis and chondrogenesis, as well as the role of c-oncogenes in the regulation of proliferation and/or cell diversification. Our common model for normal cell diversification and transformation postulates that the lineage-dependent activation of cell-specific subsets of genes active in early compartments of a given lineage, are inactive in later compartments. To test this, 0-16 hour chick blastodisc cells were dissociated and cultured at low density. They demonstrate that hours prior to gastrulation, and well before putative "cell-cell, epithelial-mesenchymal inductive interactions", blastodisc cells have been channeled into different, transitory, founder cells for multi-, bi-, and unipotential lineages. These findings suggest that early and late stages of diversification reflect genetically pre-programmed intracellular changes, rather than changes primarily induced by exogenous molecules. These conclusions are also consistent with the proposition that the unique phenotypic properties of any given type of transformed cell must be pre-determined by the differentiation program of its normal progenitor cell.