Evidence That a Cell-Type-Specific Efflux Pump Regulates Cell Differentiation in Dictyostelium

Abstract

We have identified a cellular efflux pump, RhT, with the properties of an MDR transporter-a type of ATP-binding cassette transporter whose substrates include small hydrophobic molecules. RhT transports rhodamine 123 (Rh123) and is inhibited by low temperature, energy poisons, and several MDR transport inhibitors, such as verapamil. All vegetative cells have RhT activity, but during development prestalk cells lose RhT activity while prespore cells retain it. We also identified several RhT inhibitors. The most effective inhibitor is the stalk cell-inducing chlorinated alkyl phenone, DIF-1. The RhT inhibitors disrupted development, to varying degrees, and induced stalk cell formation in submerged culture. The inhibitors displayed the same rank order of pharmacological efficacy for stalk cell induction as they did for Rh123 transport inhibition. We also found that cerulenin, a specific inhibitor of DIF-1 biosynthesis (R. R. Kay, 1998, J. Biol. Chem. 273, 2669-2675), abolished the induction of stalk cells by each of the RhT inhibitors, and this effect could be reversed by DIF-1. Thus, DIF-1 synthesis appears to be required for the induction of stalk cells by the RhT inhibitors. Since DIF-1 is the most potent inhibitor of RhT activity, and thus a likely transport substrate itself, we propose that RhT inhibitors induce stalk cell differentiation by blocking DIF-1 export, causing DIF-1 to build up within cells. Our results provide evidence for a prespore-specific efflux pump that regulates cell fate determination, perhaps by regulating the cellular concentration of DIF-1.

Embryo stability and vulnerability in an always changing world

“…Examples are seen in Dictyostelium, where PGP transporters efflux morphogens signaling stalk cell differentiation (25) and in Arabidopsis, where MRP transporters direct root development by efflux-mediated establishment of auxin gradients (26). In sea urchin embryos, a major MRP activity appears to be involved in regulation of cell-cycle progression, possibly through efflux of an endogenous compound(s) during early cleavages (27).…”

ATP-binding-cassette transporters in hematopoietic stem cells and their utility as therapeutical targets in acute and chronic myeloid leukemia

“…The presence of many ABC transporters with a wide variety of putative substrates in (hematopoietic) stem cells predicts that, in addition to the protection of these long-lived cells against naturally occurring xenobiotics, they are involved in processes that are essential or the stem cell character of these cells. A first glimpse into their putative physiological significance in these cells has come from studies in Dictyostelium demonstrating that a rhodamine-123 cellular efflux pump (RhT) with the properties of an ABC transporter prevents differentiation of prespore cells, 27 possibly by exporting differentiating factors from the cell interior. This led to the hypothesis that a cell's response to a signal that can diffuse across the plasma membrane depends, in part, on the cell's ability to remove it from the cytoplasm.…”

ATP-Binding Cassette Transporter B4 Anchors the Cell Adhesion Molecule DdCAD-1 to Cell Membrane in Dictyostelium discoideum

“…In Dictyostelium, there exist ABC transporters that were involved in the release of signals from cells [15]. 68 members were recognized in Dictyostelium ABC transporter family so far [16], and members of some ABCB families were capable of transporting peptides that lack classical export signals [17].…”