Troglitazone induces differentiation in Trypanosoma brucei.
Trypanosoma brucei, a protozoan parasite causing sleeping sickness, is transmitted by the tsetse fly and undergoes a complex lifecycle including several defined stages within the insect vector and its mammalian host. In the latter, differentiation from the long slender to the short stumpy form is induced by a yet unknown factor of trypanosomal origin. Here we describe that some thiazolidinediones are also able to induce differentiation. In higher eukaryotes, thiazolidinediones are involved in metabolism and differentiation processes mainly by binding to the intracellular receptor peroxisome proliferator activated receptor gamma. Our studies focus on the effects of troglitazone on bloodstream form trypanosomes. Differentiation was monitored using mitochondrial markers (membrane potential, succinate dehydrogenase activity, inhibition of oxygen uptake by KCN, amount of cytochrome transcripts), morphological changes (Transmission EM and light microscopy), and transformation experiments (loss of the Variant Surface Glycoprotein coat and increase of dihydroliponamide dehydrogenase activity). To further investigate the mechanisms responsible for these changes, microarray analyses were performed, showing an upregulation of expression site associated gene 8 (ESAG8), a potential differentiation regulator.
Denninger
Viola
V
Interfakultäres Institut für Biochemie, Universität Tübingen, Hoppe-Seyler-Str. 4, D-72076 Tübingen, Germany.
Figarella
Katherine
K
Schönfeld
Caroline
C
Brems
Stefanie
S
Busold
Christian
C
Lang
Florian
F
Hoheisel
Jörg
J
Duszenko
Michael
M
D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D019069:Cell Respiration / Q000187:drug effects* / Q000502:physiology; D048430:Cell Shape / Q000187:drug effects / Q000502:physiology; D002839:Chromans / Q000494:pharmacology*; D003580:Cytochromes / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D015800:Protozoan Proteins / Q000235:genetics; D013385:Succinate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D014353:Trypanosomiasis, African / Q000188:drug therapy; D015854:Up-Regulation / Q000235:genetics
D015415:Biomarkers; D002839:Chromans; D003580:Cytochromes; D007004:Hypoglycemic Agents; D008562:Membrane Glycoproteins; D015800:Protozoan Proteins; D045162:Thiazolidinediones; C066671:ESAG 8 protein, Trypanosoma brucei; D013385:Succinate Dehydrogenase; D000077288:Troglitazone