MECHANISMS OF TRANSFORMATION OF HEMATOPOIETIC CELLS

描述：（改编自研究者摘要）在美国，那里 每年有超过一百万的新癌症病例， 大约50万人死亡。 在不久的将来， 比其他任何疾病都要多。 远程 拟议研究的目标是增加我们对以下问题的了解 造血细胞生长和恶性转化创造新的 用于治疗瘤形成的疗法。 这个提议的中心主题是要理解 Raf激酶的激活可导致 尼古丁依赖与造血细胞凋亡的预防 生长和恶性转化，以创造新的疗法， 肿瘤的治疗。 条件活性Raf激酶的能力， 其通过将活化的RAF（_Raf）等位基因与 雌激素受体（ER）激素结合结构域（_Raf：ER），以废除雌激素受体（ER）结合结构域（_Raf：ER）。 测定造血细胞的精氨酸依赖性。 两种类型的 细胞被回收，那些增殖的细胞响应于去调节的 _Raf：ER活性（雌二醇反应性）和那些没有 （雌二醇-无反应）。 制定了以下具体目标， 了解Raf激酶活性失调如何消除 药物依赖：目标1。 为了确定信号转导是否 雌二醇应答和雌二醇非应答的途径_Raf：ER克隆 在生物化学上是不同的 目标二。 确定负责的依据 A-Raf、B-Raf和Raf-1癌蛋白的不同能力， 废除对毒品的依赖和目标3。 以确定是否 Raf癌蛋白对精氨酸依赖性的消除是间接的， 需要激活额外的基因 放松管制 尼古丁依赖性和细胞凋亡已经被牵连在的病因， 许多不同类型的癌症和自身免疫性疾病， 神经退行性疾病和艾滋病。 了解这些信号 转导和凋亡途径相互影响， 我们对癌基因异常激活的后果的理解， 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.