REGULATION OF HEMATOPOIESIS BY EPIDERMAL GROWTH FACTOR RECEPTOR

在人类中，表皮生长因子受体的放大。EGFR 已在肉瘤、头部鳞状细胞癌和 颈部和胶质母细胞瘤。在鸡中，致癌基因v-ergB负责 治疗红细胞性白血病。V-ergB癌蛋白与 鸡肉表皮生长因子受体，称为c-erbB。禽类系统比起 对人类细胞系统进行必要的遗传和分子分析 解决机械论问题，因此，大多数机械论研究都解决了 在禽类系统中已经进行了EGFR介导的肿瘤发生。 两个不同的正常鸡红系祖细胞的分析 C-erbB在红系分化中起一定作用。白血病可以是 被视为差异化的障碍，因此真正理解 只有当我们了解了白血病发生的机制 控制祖细胞的正常生长和分化， 会得白血病。在这方面，鸟类系统的独特之处在于 正常祖细胞的生长和分化可以在 在体外，它们也可以转化为白血病表型。因此， 正常细胞和白血病细胞可以比较和各种信号的作用 正常红细胞生成和维持中的转导通路 白血病的状态已经确定。因此，我们正在使用这个系统来 确定c-erb B在正常红系细胞生长和 并找出其转化的基本机制。 ErgB。我们的具体目标是： 1.两种红系的生长分化特征 祖细胞。通过以下方式确定它们是否为转换的目标细胞 V-erbB，并表征白血病转化如何改变其正常状态 成长和行为。 2.确定用于控制的信号转导通路 正常红系和转化红系的增殖分化 细胞。参与几个信号转导途径的底物将是 评估它们在c-erb和c-erbB诱导自我更新中的作用 V-erbB基因的转化。

In humans, amplification of the epidermal growth factor receptor. EGFR gene has been found in sarcomas, squamous cell carcinomas of the head and neck and glioblastomas. In chickens, the oncogene v-ergB is responsible for erythroid leukemia. The v-ergB oncoprotein is homologous to the chicken EGFR, termed c-erbB. The avian system is more amenable than the human cell systems to the genetic and molecular analysis necessary to address mechanistic questions, hence, most mechanistic studies addressing EGFR-mediated oncogenesis have been performed in the avian system. Analysis of two distinct normal chicken erythroid progenitors demonstrated that c-erbB plays a role in erythroid differentiation. Leukemia can be viewed as a block in differentiation, therefore a true understanding of leukemogenesis can only be obtained when we understand the mechanisms that control the normal growth and differentiation of the progenitor cells that become leukemic. In this regard the avian system is unique in that the growth and differentiation of the normal progenitor cells can be studied in vitro and they can also be transformed to a leukemic phenotype. Thus normal and leukemic cells can be compared and the role of various signal transduction pathways in normal erythropoiesis and in the maintenance of the leukemic state determined. Therefore we are using this system to determine the role of c-erbB in normal erythroid cell growth and differentiation and to identify the basic mechanism of transformation by v- ergB. Our specific aims are: 1. To characterize the growth and differentiation of the two erythroid progenitor cells. Determine if they are target cells for transformation by v-erbB, and characterize how leukemic transformation alters their normal growth and behavior. 2. To identify the signal transduction pathways used to control the proliferation and differentiation of normal and transformed erythroid cells. Substrates involved in several signal transduction pathways will be evaluated for their role in the induction of self-renewal by c-erbB and in transformation by v-erbB.