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

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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.