Effects of the tumor inhibitory triterpenoid avicin G on cell integrity, cytokinesis, and protein ubiquitination in fission yeast.

Abstract

Avicins comprise a class of triterpenoid compounds that exhibit tumor inhibitory activity. Here we show that avicin G is inhibitory to growth of the fission yeast Schizosaccharomyces pombe. S. pombe cells treated with a lethal concentration of avicin G (20 microM) exhibited a shrunken morphology, indicating that avicin G adversely affects cell integrity. Cells treated with a sublethal concentration of avicin G (6.5 microM) exhibited a strong cytokinesis-defective phenotype (multiseptated cells), as well as cell morphology defects. These phenotypes bear resemblance to those resulting from loss of Rho1 GTPase function in S. pombe. Indeed, Rho1-deficient S. pombe cells were strongly hypersensitive to avicin G, suggesting that the compound may perturb Rho1-dependent processes. Consistent with previously observed effects in human Jurkat T cells, avicin G treatment resulted in hyperaccumulation of ubiquitinated proteins in S. pombe cells. Interestingly, proteasome-defective S. pombe mutants were not markedly hypersensitive to avicin G, whereas an anaphase-promoting complex (mitotic ubiquitin ligase) mutant exhibited avicin G resistance, suggesting that the increase in levels of ubiquitinated proteins resulting from avicin G treatment may be due to increased protein ubiquitination, rather than inhibition of 26S proteasome activity. Mutants defective in the cAMP/PKA pathway also exhibited resistance to avicin G. Our results suggest that S. pombe will be a useful model organism for elucidating molecular targets of avicin G and serve as a guide to clinical application where dysfunctional aspects of Rho and/or ubiquitination function have been demonstrated as in cancer, fibrosis, and inflammation.

• Authors: Jordan U Gutterman, Hong T Lai, Peirong Yang, Valsala Haridas, Amos Gaikwad, Stevan Marcus
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 102 Issue 36 Pg. 12771-6 (Sep 06 2005) ISSN: 0027-8424 [Print] United States
• PMID: 16118282 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Saponins
• Schizosaccharomyces pombe Proteins
• Terpenes
• Ubiquitin
• avicin G
• Ubiquitin-Protein Ligase Complexes
• Anaphase-Promoting Complex-Cyclosome
• rho GTP-Binding Proteins
• rho1 protein, S pombe

Topics

• Anaphase-Promoting Complex-Cyclosome
• Antineoplastic Agents (pharmacology)
• Cell Membrane Permeability (drug effects)
• Cell Proliferation (drug effects)
• Cytokinesis (drug effects)
• Drug Resistance, Fungal
• Mutation (genetics)
• Protein Binding
• Saponins (pharmacology)
• Schizosaccharomyces (cytology, drug effects, genetics, metabolism)
• Schizosaccharomyces pombe Proteins
• Terpenes (pharmacology)
• Ubiquitin (metabolism)
• Ubiquitin-Protein Ligase Complexes (genetics, metabolism)
• Up-Regulation
• rho GTP-Binding Proteins (deficiency, genetics, metabolism)