Cyclic AMP-mediated suppression of normal and neoplastic B cell proliferation is associated with regulation of myc and Ha-ras protooncogenes.
Cyclic AMP functions as a negative regulator of cell proliferation in a variety of cell systems. We show here that the proliferation of normal and neoplastic B cells can be inhibited by high intracellular levels of cAMP. Thus forskolin treatment of the neoplastic B precursor cell line Reh induced a rapid increase in the cAMP level, which was followed by an accumulation of cells in the G0/G1 phase of the cell cycle over a period of 2-3 days. Similar inhibition of Reh cell proliferation after 3 days was observed whether forskolin was present continuously or only during the first 5 hr. Both c-myc and c-Ha-ras protein levels were transiently down-regulated at 4 hr of forskolin treatment, suggesting that these protooncogenes play a role in the process leading to cAMP-mediated growth cessation. Northern-blot analysis showed that the steady-state levels of c-myc RNA rapidly declined in all phases of the cell cycle, to return to control levels within a time period of 24 hr. In contrast, the c-Ha-ras mRNA level was steadily maintained. Thus the expression of c-myc and c-Ha-ras protein was regulated at different metabolic levels. The reduced proliferative capacity of the B precursor cell line in the presence of forskolin was not linked to induced differentiation. This was judged from the lack of appearance of three different B cell differentiation markers; cytoplasmic immunoglobulin heavy chain and two antigens recognized by the monoclonal antibodies B1 (CD20) and HH1 (CD37). We also showed that forskolin partially inhibited the proliferation of normal B lymphocytes stimulated by anti-immunoglobulins (anti-mu) and B cell growth factor (BCGF). The burst of c-myc mRNA during activation of normal B cells was also reduced by forskolin.
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects* / Q000473:pathology; D002453:Cell Cycle; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007945:Leukemia, Lymphoid / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc; D016283:Proto-Oncogene Proteins p21(ras); D011519:Proto-Oncogenes
D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000242:Cyclic AMP; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)