ROLE OF CAMP IN GROWTH CONTROL AND DIFFERENTIATION--GENE REGULATION

CAMP在生长控制和分化中的作用--基因调控

• 批准号: 3808517
• 负责人: Y S CHO-CHUNG
• 金额: --
• 依托单位: DIVISION OF CANCER BIOLOGY AND DIAGNOSIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3808517
• 关键词: antisense nucleic acid; biological signal transduction; cell differentiation; cyclic AMP; cyclic AMP receptors; gene expression; human tissue; neoplasm /cancer chemotherapy; neoplastic transformation; nucleotide analog; protein kinase A; receptor binding

In normal tissues, the balance between the positive and negative regulation with respect to cell proliferation is precisely controlled at the level of the cell surface, which receives extra-cellular signals, and at the intracellular level where these signals are transduced. Alterations or breakdown of these growth regulatory circuits, the growth stimulatory and growth-constraining mechanisms, are involved in triggering the process of uncontrolled outgrowth: cancer. Our hypothesis is that cAMP-dependent protein kinases are crucial effectors in tumorigenesis. cAMP acts by binding to the regulatory subunits of cAMP-dependent protein kinase. Two such subunits exist, RI and RII, which interact with a common catalytic subunit and are present in normal cells as a specific physiological ratio; departure from the normal balance of these two isoforms of the subunits may lead to the induction of malignant transformation. cAMP binds to RI and RII; however, these cAMP receptor proteins transduce opposite signals, the RI being stimulatory and the RII inhibitory of cell proliferation. This conclusion was drawn from the studies that employed independent experimental approaches: the use of site-selective cAMP analogs that, unlike parent cAMP, are able to differentiate between the binding sites on RI and RII; antisense oligonucleotides, those that are able to selectively inhibit the function of RI and RII; and transfer and overexpression of the RII gene by a retroviral vector. These studies demonstrated that restoration of the normal balance between RI and RII is of great potential in cancer therapy. Thus, these studies contribute to understanding the mechanism of cAMP control of all growth and differentiation and provide new approaches to the treatment of cancer.

在正常组织中，正负平衡 细胞增殖的调节精确控制在 细胞表面的水平，接收细胞外信号， 以及这些信号在细胞内水平的转导。 这些生长调节回路的改变或崩溃，生长 刺激和生长抑制机制，参与 引发不受控制的生长过程：癌症。 我们的假设是 cAMP 依赖性蛋白激酶至关重要 肿瘤发生中的效应子。 cAMP 通过与监管机构结合发挥作用 cAMP 依赖性蛋白激酶亚基。存在两个这样的亚基，RI 和 RII，它们与共同的催化亚基相互作用并存在 在正常细胞中作为特定的生理比例；离开 这两种亚基亚型的正常平衡可能导致 诱导恶变。 cAMP 与 RI 和 RII 结合；然而， 这些 cAMP 受体蛋白转导相反的信号，RI 是 刺激和 RII 抑制细胞增殖。 这 结论是从采用独立研究的 实验方法：使用位点选择性 cAMP 类似物， 与亲本 cAMP 不同，能够区分结合位点 关于 RI 和 RII；反义寡核苷酸，那些能够 选择性抑制RI和RII的功能；并转移和 通过逆转录病毒载体过度表达 RII 基因。 这些研究表明，恢复之间的正常平衡 RI和RII在癌症治疗中具有巨大潜力。 因此，这些研究 有助于理解cAMP控制所有生长的机制 和分化并提供新的治疗方法 癌症。