MECHANISM OF CAMP ACTION IN GROWTH CONTROL, DIFFERENTIATION, AND GENE REGULATION

在正常组织中，正负向之间的平衡 对细胞增殖的调控精确地控制在 接收细胞外信号的细胞表面的水平，以及 在细胞内的水平上，这些信号是被传递的。 这些生长调节回路的改变或故障，生长 刺激和抑制生长的机制，参与了 引发不受控制的生长过程：癌症。 我们的假设是cAMP依赖的蛋白激酶是至关重要的 肿瘤发生中的效应物。CAMP通过约束监管机构而采取行动 CAMP依赖的蛋白激酶亚基。存在两个这样的亚基，RI 和RII，它们与共同的催化亚单位相互作用，并存在 在正常细胞中作为特定的生理比率；偏离 亚基的这两种异构体的正常平衡可能导致 诱发恶性转化。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 刺激和抑制细胞增殖的RII。这 结论是从独立受雇的研究得出的 实验方法：使用位点选择性cAMP类似物， 与亲本cAMP不同，它们能够区分结合位点 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； 逆转录病毒载体过表达RI或RII基因。 这些研究表明，恢复正常的平衡 RI和RII在肿瘤治疗中具有很大的潜力。因此，这些研究 有助于理解cAMP控制细胞生长的机制 和分化，并提供了新的治疗方法 癌症。

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 RI or 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 cell growth and differentiation and provide new approaches to the treatment of cancer.