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，正面和阴性之间的平衡 关于细胞增殖的调节精确控制 接收细胞外信号的细胞表面水平， 在这些信号转导的细胞内水平上。 这些增长调节电路的改变或分解，增长 刺激和生长受限机制参与 触发不受控制的生长过程：癌症。 我们的假设是依赖cAMP的蛋白激酶是至关重要的 肿瘤发生的效应子。营地通过与监管结合而行动 cAMP依赖性蛋白激酶的亚基。存在两个这样的亚基，RI RII与共同的催化亚基相互作用并存在 在正常细胞中，作为特定的生理比率；离开 亚基的这两个同工型的正常平衡可能导致 诱导恶性转化。营地与RI和RII结合；然而， 这些cAMP受体蛋白会导致相反的信号，RI为 刺激性和RII抑制细胞增殖。 这 结论是从采用独立的研究中得出的 实验方法：使用现场选择的营地类似物， 与母体营地不同，能够区分绑定位点 在RI和RII上；反义寡核苷酸，那些能够 有选择地抑制RI和RII的功能；和转移和 通过逆转录病毒载体对RII基因的过表达。 这些研究表明，恢复正常平衡 RI和RII在癌症治疗中具有很大的潜力。 因此，这些研究 有助于理解所有增长的营地控制机制 和分化，并为治疗的新方法提供 癌症。