DIFFERENTIATION OF MEDULLARY THYROID CARCINOMA CELLS

描述：(改编自调查人员的摘要) 这一应用试图阐明神经内分泌的控制 正常分泌降钙素的甲状腺C细胞的分化及其意义 肿瘤性甲状腺髓样癌(MTC)。 了解这种控制可以为事件提供重要的洞察力 在肿瘤的发生和发展中起重要作用。甲状腺髓样癌是 这是一个很好的研究模型，因为定义了进展的阶段 涉及神经内分泌分化特征的丧失，包括 已经确定了生产降钙素的能力。我们有 建立了研究MTC分化和分化步骤的体外系统 进步。培养中的MTC细胞可以根据以下方面进行分化 正常C细胞的许多特征，包括降钙素升高 基因表达，化学或ras或raf癌基因 引言。目前的提案将进一步说明这些特点 根据细胞生物学、生物化学和分子生物学的研究结果， 集中在调节诱导的分子机制上 差异化。建议的研究不仅对 确定可能参与MTC进展的过程，但 也用于确定神经内分泌所涉及的因素和途径 分化，并进一步阐明ras和raf的机制。 癌基因在细胞中的作用。 1.两个与ras/raf特异结合的克隆蛋白 降钙素基因的反应元件，将被描述为 它们的功能是转录因子。监管机制 这可能允许这些蛋白质在MTC和其他类型的细胞中介导 对ras或raf的表型反应(分化或转化) 将会被检查。 2.遗传性MTC中突变激活的ret癌基因， 在许多散发性MTC中，在RAF介导的过程中是沉默的 MTC细胞在培养过程中的分化。这其中的机制 我们将探讨静音问题。将对该可能性进行测试 静音是MTC终端的一个必要或充分步骤 差异化。这可能具有重要的治疗意义 MTC。将确定RET是否可以在其他小区类型中被静音， 以及其他酪氨酸激酶是否可以通过类似的机制沉默。如果 其他酪氨酸激酶可以被沉默，这也可以提供一种 几种常见癌症的治疗靶点，其中过表达 酪氨酸激酶有助于癌症的生长。

DESCRIPTION: (adapted from the investigator's abstract) The studies in this application seek to elucidate the control of neuroendocrine differentiation in normal calcitonin producing thyroid C-cells and their neoplastic counterpart, medullary thyroid carcinoma (MTC). Understanding this control could provide important insight for events in tumor development and progression. Medullary thyroid carcinoma is a good model for this study, since defined stages of progression which involve loss of neuroendocrine differentiation features, including capacity for calcitonin production, have been identified. We have developed an in vitro system to study steps of MTC differentiation and progression. MTC cells in culture can be differentiated with respect to many characteristics of normal C-cells, including increased calcitonin gene expression, either chemically or by ras or raf oncogene introduction. The current proposal will further characterize these findings, by cell biology, biochemistry, and molecular biology, concentrating on the molecular mechanisms regulating the induced differentiation. The studies proposed will be important not only for identifying the processes which may be involved in MTC progression, but also for defining the factors and pathways involved in neuroendocrine differentiation, and further elucidating the mechanisms of ras and raf oncogene function in cells. 1. Two cloned proteins, which bind specifically to the ras/raf responsive elements of the calcitonin gene, will be characterized for their function as transcription factors. The mechanisms of regulation which may allow these proteins, in MTC and other cell types, to mediate phenotypic responses to ras or raf (differentiation or transformation) will be examined. 2. The ret oncogene, which is activated by mutation in hereditary MTC, and in many cases of sporadic MTC, is silenced during raf-mediated differentiation of MTC cells in culture. The mechanisms of this silencing will be explored. The possibility will be tested that ret silencing is a necessary or sufficient step for MTC terminal differentiation. This could have important therapeutic implications in MTC. It will be determined if ret can be silenced in other cell types, and if other tyrosine kinases can be silenced by similar mechanisms. If other tyrosine kinases can be silenced, this could also provide a therapeutic target in several common cancers, in which overexpression of tyrosine kinases contributes to cancer growth.