REGULATION OF HEMATOPOIESIS BY EPIDERMAL GROWTH FACTOR RECEPTOR

人类表皮生长因子受体的扩增。 EGFR 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 治疗红细胞白血病 v-ergB癌蛋白与 鸡表皮生长因子受体，称为c-erbB。 鸟类系统比鸟类系统更容易控制 人类细胞系统的遗传和分子分析， 解决机械问题，因此，大多数机械研究解决 EGFR介导的肿瘤发生已在禽类系统中进行。 两种不同的正常鸡红系祖细胞的分析表明， c-erbB在红系分化中起作用。 白血病可以 被视为分化的障碍，因此， 只有当我们了解了 控制祖细胞的正常生长和分化， 变成白血病 在这方面，鸟类系统是独一无二的， 正常祖细胞的生长和分化可以在 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进行比较和各种信号的作用 在正常红细胞生成和维持 白血病的症状 因此，我们使用这个系统， 确定c-erbB在正常红系细胞生长中的作用， 分化，并确定通过v- ergB. 我们的具体目标是： 1. 为了表征两种红系细胞的生长和分化， 祖细胞 通过以下方式确定它们是否是转化的靶细胞 v-erbB，并描述白血病转化如何改变他们的正常 成长和行为。 2. 为了确定用于控制细胞凋亡的信号转导途径， 正常和转化红细胞的增殖和分化 细胞 参与几种信号转导途径的底物将被 评价了它们在c-erbB诱导自我更新和 通过v-erbB进行转化。

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.