Abstract
Tetrahymena is able to adapt to the presence of sublethal concentrations of many drugs which inhibit a wide variety of cellular functions. In spite of the generality of this phenomenon in Tetrahymena, the mechanism of adaptation at the cellular and molecular levels is unknown. This study deals mainly with adaptation to the protein synthesis inhibitors, cycloheximide and emetine. The physiological response of Tetrahymena to sublethal concentrations of these drugs is an immediate cessation of cell division for a period of time dependent on the drug concentration, followed by an abrupt resumption of exponential growth at a constant rate. By measuring the length of the growth lags under a variety of experimental conditions, we have confirmed several observations made by Frankel and coworkers, and provide evidence for two new phenomena associated with adaptation to cycloheximide: (a) adaptation to cycloheximide also results in adaptation of cells to emetine, another protein synthesis inhibitor not closely related structurally to cycloheximide. We have termed this phenomenon cross adaptation, (b) exposure to concentrations of cycloheximide too low to cause any growth lags or inhibition of protein synthesis significantly shortens the time required by cells to adapt to higher concentrations of cycloheximide. We have termed this phenomenon facilitation. Facilitation shows some degree of specificity in that facilitation with cycloheximide has no effect on adaptation to emetine. From this, we infer the existence of two distinct systems involved in adaptation to cycloheximide, one of which shows a higher degree of specificity towards cycloheximide than the other. We also show that transfer of adapted or facilitated cells to drug-free medium results in a gradual but complete resensitization. The kinetics of resensitization suggest that the cellular machinery responsible for adaptation and facilitation does not leave the cell, but is simply diluted out during cell division.
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Selected References
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- Allen N. E., Suyama Y. Protein synthesis in vitro with Tetrahymena mitochondrial ribosomes. Biochim Biophys Acta. 1972 Feb 15;259(3):369–377. doi: 10.1016/0005-2787(72)90311-5. [DOI] [PubMed] [Google Scholar]
- Davies M. E., Exworth C. P. Transient inhibition by cycloheximide of protein synthesis in cultured plant cell suspensions: a dose response paradox. Biochem Biophys Res Commun. 1973 Feb 20;50(4):1075–1080. doi: 10.1016/0006-291x(73)91516-7. [DOI] [PubMed] [Google Scholar]
- Frankel J. An analysis of the recovery of tetrahymena from effects of cycloheximide. J Cell Physiol. 1970 Aug;76(1):55–63. doi: 10.1002/jcp.1040760109. [DOI] [PubMed] [Google Scholar]
- Frankel J. The effect of nucleic acid antagonists on cell division and oral organelle development in Tetrahymena pyriformis. J Exp Zool. 1965 Jun;159(1):113–147. doi: 10.1002/jez.1401590109. [DOI] [PubMed] [Google Scholar]
- Frankel J. The relationship of protein synthesis to cell division and oral development in synchronized Tetrahymena pyriformis GL-C: an analysis employing cycloheximide. J Cell Physiol. 1969 Oct;74(2):135–148. doi: 10.1002/jcp.1040740205. [DOI] [PubMed] [Google Scholar]
- Grollman A. P., Huang M. T. Inhibitors of protein synthesis in eukaryotes: tools in cell research. Fed Proc. 1973 Jun;32(6):1673–1678. [PubMed] [Google Scholar]
- Grollman A. P. Inhibitors of protein biosynthesis. V. Effects of emetine on protein and nucleic acid biosynthesis in HeLa cells. J Biol Chem. 1968 Aug 10;243(15):4089–4094. [PubMed] [Google Scholar]
- Grollman A. P. Structural basis for inhibition of protein synthesis by emetine and cycloheximide based on an analogy between ipecac alkaloids and glutarimide antibiotics. Proc Natl Acad Sci U S A. 1966 Dec;56(6):1867–1874. doi: 10.1073/pnas.56.6.1867. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Heyer C. B., Frankel J. The kinetics of resensitization of Tetrahymena following recovery from effects of cycloheximide. J Cell Physiol. 1971 Dec;78(3):411–418. doi: 10.1002/jcp.1040780310. [DOI] [PubMed] [Google Scholar]
- Obrig T. G., Culp W. J., McKeehan W. L., Hardesty B. The mechanism by which cycloheximide and related glutarimide antibiotics inhibit peptide synthesis on reticulocyte ribosomes. J Biol Chem. 1971 Jan 10;246(1):174–181. [PubMed] [Google Scholar]
- Rasmussen L., Zeuthen E. Cell division in Tetrahymena adapting to p-dl-fluorophenylalanine. Exp Cell Res. 1966 Feb;41(2):462–465. doi: 10.1016/s0014-4827(66)80154-4. [DOI] [PubMed] [Google Scholar]
- Roberts C. T., Jr, Orias E. A cycloheximide-resistant mutant of Tetrahymena pyriformis. Exp Cell Res. 1973 Oct;81(2):312–316. doi: 10.1016/0014-4827(73)90520-x. [DOI] [PubMed] [Google Scholar]
- Roberts C. T., Jr, Orias E. Cytoplasmic inheritance of chloramphenicol resistance in tetrahymena. Genetics. 1973 Feb;73(2):259–272. doi: 10.1093/genetics/73.2.259. [DOI] [PMC free article] [PubMed] [Google Scholar]