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Molecular Mechanisms of Haemopoietic Growth Factor Action
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Molecular Mechanisms of Haemopoietic Growth Factor Action
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Dissertation
Molecular Mechanisms of Haemopoietic Growth Factor Action
1991
Overview
Interleukin-3 (IL-3) stimulates the survival and proliferation of the FDCP-Mix 1 multipotent stem cell line. The possible involvement of guanyl nucleotide regulatory protein(s) in the IL-3 stimulated proliferative response has been evaluated. Pertussis toxin (PT) can partially inhibit IL-3 stimulated DNA synthesis and this inhibition is bypassed by TPA. The ADP-ribosylation of the PT substrate G protein in vivo is complete in 2 hours without concomitant inhibition of IL-3 stimulated hexose transport and Na+/H+ exchange. When loaded into FDCP-Mix 1 cells fluoroaluminate and CTP-∂-S, which can directly activate G proteins, are not capable of mimicking the effects of IL-3. Evidence is also presented that IL-3 does not stimulate a membrane-bound high affinity GTPase activity in the FDCP-Mix 1 cell line. These data suggest that a PT substrate G protein(s) can influence the IL-3 signalling cascade in an indirect or permissive manner, but that the IL-3 receptor does not directly couple to this G protein.IL-3 stimulates a transient fall in intracellular cyclic AMP levels in the absence of a cyclic AMP phosphodiesterase inhibitor which is not observed in the presence of the inhibitor. However, IL-3 has no long-term effects on the cyclic AMP levels of the FDCP-Mix 1 cells. The cells are shown to be competent for receptor-mediated increases in adenylate cyclase activity in response to PGE2 and NECA respectively. Both of these agents markedly elevate cyclic AMP levels and are shown to inhibit IL-3 stimulated DNA synthesis. Furthermore, long-term incubations with either cholera toxin or pertussis toxin also causes an increase in intracellular cyclic AMP levels. Thus, whilst there is no evidence of a second messenger role for cyclic AMP in IL-3 action, elevated levels of the cyclic nucleotide appeared to have an inhibitory effect on IL-3 stimulated proliferation.Also, a highly enriched population (>90%) of Granulocyte-Macrophage Colony-Forming Cells (GM-CFC) was prepared from bone marrow. These cells respond to Stem Cell Factor (SCF) and M-CSF by proliferation and development, forming granulocytic and monocytic cells respectively. Characterization of the molecular signals elicited by SCF in GM-CFC shows that an amiloride-sensitive Na+/H+ antiport is activated without inositol lipid hydrolysis. Furthermore, SCF-induced DNA synthesis is not sensitive to pertussis toxin. The potential of deciphering the molecular basis of lineage-restricted development by comparing the signalling events elicited by SCF and M-CSF in this cell population is highlighted.
