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Self-regulating systems often use robust oscillatory circuits. One such system controls the chemotactic signaling mechanism of Dictyosteiium, where pulses of adenosine 3',5'-monophosphate (cAMP) are generated with a periodicity of 7 minutes. We have observed spontaneous oscillations in activation of the mitogenactivated protein (MAP) kinase ERK2 that occur in phase with peaks of cAMP, and we show that ERK2 modulates cAMP levels through the phosphodiesterase RegA. Computer modeling and simulations of the underlying circuit faithfully account for the ability of the cells to spontaneously generate periodic pulses during specific stages of development. Similar oscillatory processes may occur in cells of many different species. [ABSTRACT FROM AUTHOR]

It has been previously reported that the differentiating wild-type cells of Dictyostelium discoideum secrete a diffusible factor or factors that are able to rescue the developmental defect in the mutant lacking extracellular signal-regulated kinase 2 (ERK2), encoded by the gene erkB. In the present study, it is demonstrated that differentiation-inducing factor-1 (DIF-1) for stalk cells can mimic the role of the factor(s) and the mechanism of the action of DIF-1 in the erkB null mutant is also discussed. The mutant usually never forms multicellular aggregates, because of its defect in cyclic adenosine monophosphate (cAMP) signaling. In the presence of 100 nM DIF-1, however, the mutant cells formed tiny slugs, which eventually developed into small fruiting bodies. In contrast, DIF-1 never rescued the developmental arrest of other Dictyostelium mutants lacking adenylyl cyclase A (ACA), cAMP receptors cAR1 and cAR3, heterotrimeric G-protein, the cytosolic regulator of ACA, or the catalytic subunit of cAMP-dependent protein kinase (PKA-C). Most importantly, it was found that DIF-1 did not affect the cellular cAMP level, but rather elevated the transcriptional level of pka during the development of erkB null cells. These results suggest that DIF-1 may rescue the developmental defect in erkB null cells via the increase in PKA activity, thus giving the first conclusive evidence that DIF-1 plays a crucial role in the early events of Dictyostelium development as well as in prestalk and stalk cell induction. [ABSTRACT FROM AUTHOR]

Mitogen-activated protein (MAP)-kinase extracellular signal regulated kinase (ERK2) is essential for regulation of the intracellular cyclic adenosine monophosphate (cAMP) level in Dictyostelium. The mutant lacking ERK2, erk2-null, is arrested at the pre-aggregation stage, but develops into a fruiting body in a mixed population of wild-type and mutant cells. This fact implies that wild-type cells provide a certain factor that is missing in erk2-null. It was clarified that both wild-type strains KAx3 and Ax2 secreted a diffusible factor that enables erk2-null to develop. The fruiting body formed from erk2-null cells was smaller than that formed by the wild-type cells and consisted of a small sorus supported by a slender stalk with a single row of vacuolated stalk cells. The resulting spores were able to germinate and multiply on a bacterial lawn, but they were unable to develop unless the factor was provided. After 8 h of starvation, wild-type cells started to secrete the factor, which had a molecular mass of less than 3 kDa and was heat stable. The effect of this factor could not be mimicked by either cAMP or folate. Adenylyl cyclase A and cell surface cAMP receptors cAR1 and cAR3 were all indispensable components for the factor to function. Considering the molecular mass and the mode of action, this factor could be a novel one. Possible targets of this factor are discussed in terms of cAMP-dependent protein kinase activation. [ABSTRACT FROM AUTHOR]

Differentiation-inducing factor-1 (DIF-1; 1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl)hexan-1-one) is a putative morphogen that induces stalk-cell formation in the cellular slime mold Dictyostelium discoideum. DIF-1 has previously been shown to suppress cell growth in mammalian cells. In this study, we examined the effects of DIF-1 on the progesterone-induced germinal vesicle breakdown in Xenopus laevis, which is thought to be mediated by a decrease in intracellular cAMP and the subsequent activation of mitogen-activated protein kinase (MAPK) and maturation-promoting factor, a complex of cdc2 and cyclin B, which regulates germinal vesicle breakdown. DIF-1 at 10–40 μM inhibited progesterone-induced germinal vesicle breakdown in de-folliculated oocytes in a dose-dependent manner. Progesterone-induced cdc2 activation, MAPK activation, and c-Mos accumulation were inhibited by DIF-1. Furthermore, DIF-1 was found to inhibit the progesterone-induced cAMP decrease in the oocytes. These results indicate that DIF-1 inhibits progesterone-induced germinal vesicle breakdown possibly by blocking the progesterone-induced decrease in [cAMP]i and the subsequent events in Xenopus oocytes. [Copyright &y& Elsevier]