MECHANISMS OF TRANSFORMATION OF HEMATOPOIETIC CELLS

描述：(改编自调查人员的摘要)在美国，那里 每年有100多万新的癌症病例导致 大约有50万人死亡。在不久的将来，会有更多的钱 花在癌症治疗上的钱比其他任何疾病都多。长距离的 拟议研究的目标是增加我们对 造血细胞生长和恶变创造新奇 治疗肿瘤的疗法。 这项提议的中心主题是理解反常的 Raf激酶的激活可导致 细胞因子依赖与造血细胞凋亡的预防 生长和恶性转化为癌症创造新的治疗方法 肿瘤的治疗。条件性激活的Raf激酶的能力， 它们是由激活的RAF(_Raf)等位基因与 雌激素受体(ER)激素结合域(_Raf：ER)，以消除 测定造血细胞的细胞因子依赖性。两种类型的 细胞被恢复，那些在放松管制后增殖的细胞 _Raf：ER活性(雌二醇反应)和那些没有反应的 (雌二醇--无反应)。制定了以下具体目标，以 了解解除管制的Raf激酶活性如何消除 细胞因子依赖：目的1.确定信号转导是否 雌激素反应性和非反应性_Raf：ER克隆中的通路 在生物化学上是不同的。目标2.确定负责的基础 A-Raf、B-Raf和Raf-1癌蛋白对肿瘤细胞的分化能力 取消对细胞因子的依赖和目标3。确定是否 Raf癌蛋白消除细胞因子依赖是间接的和 需要激活更多的基因。放松管制 细胞因子依赖和细胞凋亡参与了急性髓细胞白血病的发病机制。 许多不同类型的癌症和自身免疫性疾病以及 神经退行性疾病和艾滋病。了解这些信号是如何发出的 转导和凋亡途径相互影响将进一步 我们对癌基因异常激活的后果的理解和 肿瘤进展。

DESCRIPTION: (adapted from the investigator's abstract) In the US., there are over one million new cancer cases each year which result in approximately one-half million deaths. In the near future more money will be expended on cancer treatment than any other disease. The long-range goals of the proposed studies are to increase our understanding of hematopoietic cell growth and malignant transformation to create novel therapies for the treatment of neoplasia. The central theme of this proposal is to understand how the aberrant activation of the Raf kinases can result in the abrogation of cytokine-dependency and the prevention of apoptosis in hematopoietic cell growth and malignant transformation to create novel therapies for the treatment of neoplasia. The abilities of conditionally active Raf kinases, which were generated by the fusion of the activated RAF (_Raf) alleles with the estrogen-receptor (ER) hormone binding domain (_Raf:ER), to abrogate the cytokine-dependency of hematopoietic cells were determined. Two types of cells were recovered, those which proliferated in response to deregulated _Raf:ER activity (estradiol-responsive) and those which did not (estradiol-non-responsive). The following specific aims were developed to understand how deregulated Raf kinase activity can abrogate cytokine-dependency: Aim 1. To determine whether the signal transduction pathways in estradiol-responsive and estradiol-non-responsive _Raf:ER clones are biochemically different. Aim 2. To determine the basis responsible for the differential abilities of the A-Raf, B-Raf and Raf-1 oncoproteins to abrogate the cytokine-dependency and Aim 3. To determine whether the abrogation of cytokine-dependency by the Raf oncoprotein is indirect and requires the activation of additional genes. Deregulation of cytokine-dependency and apoptosis have been implicated in the etiology of many different types of cancer and autoimmune diseases as well as neurodegenerative diseases and AIDS. An understanding of how these signal transduction and apoptotic pathways impinge upon one another will further our comprehension of the consequences of abnormal oncogene activation and tumor progression.