Inhibition of HSP90 in Trypanosoma cruzi induces a stress response but no stage differentiation.
The 90-kDa heat shock proteins (HSP90) are important in the regulation of numerous intracellular processes in eukaryotic cells. In particular, HSP90 has been shown to be involved in the control of the cellular differentiation of the protozoan parasite Leishmania donovani. We investigated the role of HSP90 in the related parasite Trypanosoma cruzi by inhibiting its function using geldanamycin (GA). GA induced a dose-dependent increase in heat shock protein levels and a dose-dependent arrest of proliferation. Epimastigotes were arrested in G(1) phase of the cell cycle, but no stage differentiation occurred. Blood form trypomastigotes showed conversion towards spheromastigote-like forms when they were cultivated with GA, but differentiation into epimastigotes was permanently blocked. We conclude that, similar to leishmanial HSP90, functional HSP90 is essential for cell division in T. cruzi and serves as a feedback inhibitor in the cellular stress response. In contrast to L. donovani cells, however, T. cruzi cells treated with GA do not begin to differentiate into relevant life cycle stages.
Graefe
Sebastian E B
SE
Department of Medical Microbiology and Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
Wiesgigl
Martina
M
Gaworski
Iris
I
Macdonald
Andrea
A
Clos
Joachim
J
D000818:Animals; D016227:Benzoquinones; D002453:Cell Cycle; D002454:Cell Differentiation; D002455:Cell Division; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D016193:G1 Phase; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D015151:Immunoblotting; D047029:Lactams, Macrocyclic; D008855:Microscopy, Electron, Scanning; D011809:Quinones / Q000494:pharmacology; D013997:Time Factors; D014349:Trypanosoma cruzi / Q000378:metabolism*
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011809:Quinones; C001277:geldanamycin