Adenosine 3':5' monophosphate (cAMP) plays a pivotal role in the regulation of cell growth, gene expression, and metabolism. Purposeful modulation of cellular function has been achieved with the pharmacologic tools currently available for manipulating intracellular cAMP levels, but their numerous drawbacks have limited the practical therapeutic application of this otherwise promising principle. We have recently been working with a unique toxin, elaborated by Bordetella pertussis bacteria, which is an invasive adenylate cyclase. This enzyme will penetrate human phagocytes and generate therein unprecedented amounts of cAMP. Because of its unique-mechanism and potency, this toxin seems a promising tool for investigating the role of cAMP in regulation of growth and differentiation. Indeed, preliminary work documents the abililty of this toxin to cause large cAMP elevations in three neoplastic mammalian cell lines; in each case, concomitant growth inhibition, differentiation, or decreased maligant behavior in biologic assays occurs. The proposed research will employ this novel toxin to examine the effects of large cAMP elevations on growth and phenotypic expression in normal hematopoietic precursors and in transformed cells. We will characterize more fully the nature of the phenotypic alterations previously noted in neoplastic cells and determine their relationship to altered neoplastic behavior in vivo. In pursuing these investigative goals, the candidate will exploit his previous experience in hematopoetic and neoplastic cell culture techniques. Moreover, he will have immediate access to progressively more purified toxin preparations and new information on toxin function as a result of his close collaborative relationship with those who first elucidated its mechanism. Finally, he will enjoy the guidance of experts in relevant disciplines and the sponsorship of a senior researcher with a proven ability to foster the development of independent investigators. These studies will offer insights into the relationship between cAMP and phenotypic expression in mammalian cells. Moreover, they will demonstrate the utility of this toxin as a tool for investigating the role of cAMP in the regulation of cellular functions.
| Slungaard, A; Vercellotti, G M; Walker, G et al. (1990) Tumor necrosis factor alpha/cachectin stimulates eosinophil oxidant production and toxicity towards human endothelium. J Exp Med 171:2025-41 |
