CONVERSION OF EMBRYONIC CELLS INTO TRANSFORMED CELLS

调节正常细胞出现的细胞内控制 决定性的肌肉、软骨或色素细胞可能产生肿瘤细胞。 从Boveri的60多年来，他们的故障就一直在讨论 那是以前的事了。为此，TPA、EMS、pp60v-src和BrUdR对 原代培养成肌细胞、成软骨细胞和成软骨细胞的分化程序 黑素生成细胞的研究。这4个多效性分子，每个都有一个 不同的初始细胞内目标，共享一个显著的特性- 它们选择性地、但可逆地阻止该子集转录 定义处理细胞分化程序的基因。这些 得出的结论如下：(A)细胞特异性合成 蛋白质，以及(B)这些细胞特异的mRNAs在 处理过的细胞。正常细胞分化的脆弱性 这些药物的程序不能归因于普遍的细胞毒性 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 在调控“家庭”分子的背景下，这一点令人震惊。 这些实验也为研究人类免疫缺陷提供了异常有利的模型。 正常的肌原纤维形成和软骨形成，以及 C-癌基因在细胞增殖和/或细胞多样化调控中的作用。 我们正常细胞分化和转化的共同模型 假设依赖世系的细胞特异性亚群的激活 在特定谱系的早期隔间活跃的基因中，在 稍后的车厢。为了测试这一点，0-16小时的鸡囊胚盘细胞 分离培养，低密度培养。他们证明了几个小时前 到原肠发育，早在所谓的“细胞-细胞， 上皮-间充质诱导相互作用“，胚盘细胞 被引导到不同的、短暂的、创始细胞，用于多、双、和 单潜能血统。这些发现表明，早期和晚期 的多样性反映了遗传预先编程的细胞内 变化，而不是主要由外源分子引起的变化。 这些结论也与以下命题相一致，即 任何给定类型的转换细胞的表型属性必须是 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.