Cholera toxin and phorbol diesters synergistically modulate murine hematopoietic progenitor cell proliferation

Little information exists concerning the role of guanine nucleotide-binding proteins (GNBP) in hematopoietic progenitor cell proliferation. We hypothesized that GNBP-mediated activation of adenylate cyclase plays an important role in factor-driven hematopoietic cell proliferation. Using cholera toxin and other probes of the cyclase system, we observe that cyclase activation results in a lineage-specific amplification of megakaryocytic progenitor cell numbers, an intermediate effect on erythroid progenitors, and, conversely, an inhibition of granulocytic colony formation. The effect of GNBP activation is synergistic with, and dependent upon, concomitant activation of the cells with phorbol diesters. This suggests a role for both calcium-dependent mechanisms, such as protein kinase C activation, and for other processes mediated by GNBP and cyclic AMP. The use of an intracellular calcium antagonist (Quin-2) partially abrogates the GNBP-mediated response, confirming that the effects of GNBP activation involve both calcium-dependent and calcium-independent processes. We conclude that hematopoietic progenitor cells are influenced by lineage-specific alterations in GTP-binding protein function, which affects both adenylate cyclase activity and calcium homeostasis.