Abstract
Yeast is widely used as a model organism for investigating many aspects of eukaryotic cell biology. It combines a high level of conservation between its cellular processes and those of mammalian cells with advantages such as simple growth requirements, rapid cell division, ease of genetic manipulation and a wealth of experimental tools for genome-wide analysis of biological functions. How can these advantages be put to use in anticancer drug discovery?
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References
Marton, M. J. et al. Drug target validation and identification of secondary drug target effects using DNA microarrays. Nature Med. 4, 1293–1301 (1998).
Parsons, A. B. et al. Integration of chemical-genetic and genetic interaction data links bioactive compounds to cellular target pathways. Nature Biotechnol. 22, 62–69 (2004).
Birrell, G. W. et al. A genome-wide screen in Saccharomyces cerevisiae for genes affecting UV radiation sensitivity. Proc. Natl Acad. Sci. USA 98, 12608–12613 (2001).
Tong, A. H. et al. Global mapping of the yeast genetic interaction network. Science 303, 808–813 (2004).
Lum, P. Y. et al. Discovering modes of action for therapeutic compounds using a genome-wide screen of yeast heterozygotes. Cell 116, 121–137 (2004).
Ubersax, J. A. et al. Targets of the cyclin-dependent kinase Cdk1. Nature 425, 859–864 (2003).
von Mering, C. et al. Comparative assessment of large-scale data sets of protein–protein interactions. Nature 417, 399–403 (2002).
Hartwell, L. H. et al. Integrating genetic approaches into the discovery of anticancer drugs. Science 278, 1064–1068 (1997).
Gaber, R. F. et al. The yeast gene ERG6 is required for normal membrane function but is not essential for biosynthesis of the cell-cycle-sparking sterol. Mol. Cell. Biol. 9, 3447–3456 (1989).
Balzi, E. & Goffeau, A. Yeast multidrug resistance: the PDR network. J. Bioenerg. Biomembr. 27, 71–76 (1995).
Tugendreich, S. et al. A streamlined process to phenotypically profile heterologous cDNAs in parallel using yeast cell-based assays. Genome Res. 11, 1899–1912 (2001).
Perkins, E. et al. Novel inhibitors of poly(ADP-ribose) polymerase/PARP1 and PARP2 identified using a cell-based screen in yeast. Cancer Res. 61, 4175–4183 (2001).
Althaus, F. R. & Richter, C. ADP-ribosylation of proteins. Enzymology and biological significance. Mol. Biol. Biochem. Biophys. 37, 1–237 (1987).
Tentori, L. et al. Systemic administration of GPI 15427, a novel poly(ADP-ribose) polymerase-1 inhibitor, increases the antitumor activity of temozolomide against intracranial melanoma, glioma, lymphoma. Clin. Cancer Res. 9, 5370–5379 (2003).
Ortega, S., Malumbres, M. & Barbacid, M. Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim. Biophys. Acta 1602, 73–87 (2002).
Polyak, K. et al. p27Kip1, a cyclin–Cdk inhibitor, links transforming growth factor-β and contact inhibition to cell cycle arrest. Genes Dev. 8, 9–22 (1994).
Quelle, D. E. et al. Cloning and characterization of murine p16INK4a and p15INK4b genes. Oncogene 11, 635–645 (1995).
Liu, G. et al. A Phase II trial of flavopiridol (NSC #649890) in patients with previously untreated metastatic androgen-independent prostate cancer. Clin. Cancer Res. 10, 924–928 (2004).
Moorthamer, M. et al. The p16INK4A protein and flavopiridol restore yeast cell growth inhibited by Cdk4. Biochem. Biophys. Res. Commun. 250, 791–797 (1998).
Scorrano, L. & Korsmeyer, S. J. Mechanisms of cytochrome c release by proapoptotic BCL-2 family members. Biochem. Biophys. Res. Commun. 304, 437–444 (2003).
Xu, Q. & Reed, J. C. Bax inhibitor-1, a mammalian apoptosis suppressor identified by functional screening in yeast. Mol. Cell 1, 337–346 (1998).
Hake, S. B., Xiao, A. & Allis, C. D. Linking the epigenetic 'language' of covalent histone modifications to cancer. Br. J. Cancer 90, 761–769 (2004).
Li, E., Bestor, T. H. & Jaenisch, R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69, 915–926 (1992).
Shore, D., Squire, M. & Nasmyth, K. A. Characterization of two genes required for the position-effect control of yeast mating-type genes. EMBO J. 3, 2817–2823 (1984).
Brachmann, C. B. et al. The SIR2 gene family, conserved from bacteria to humans, functions in silencing, cell cycle progression, and chromosome stability. Genes Dev. 9, 2888–2902 (1995).
Singer, M. S. et al. Identification of high-copy disruptors of telomeric silencing in Saccharomyces cerevisiae. Genetics 150, 613–632 (1998).
Feng, Q. et al. Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain. Curr. Biol. 12, 1052–1058 (2002).
Rine, J. & Herskowitz, I. Four genes responsible for a position effect on expression from HML and HMR in Saccharomyces cerevisiae. Genetics 116, 9–22 (1987).
Vaziri, H. et al. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107, 149–159 (2001).
Luo, J. et al. Negative control of p53 by Sir2α promotes cell survival under stress. Cell 107, 137–148 (2001).
Bereshchenko, O. R., Gu, W. & Dalla-Favera, R. Acetylation inactivates the transcriptional repressor BCL6. Nature Genet. 32, 606–613 (2002).
Pasqualucci, L. et al. Mutations of the BCL6 proto-oncogene disrupt its negative autoregulation in diffuse large B-cell lymphoma. Blood 101, 2914–2923 (2003).
van Leeuwen, F. & Gottschling, D. E. Assays for gene silencing in yeast. Methods Enzymol. 350, 165–186 (2002).
Bedalov, A. et al. Identification of a small molecule inhibitor of Sir2p. Proc. Natl Acad. Sci. USA 98, 15113–15118 (2001).
Bedalov, A. et al. NAD+-dependent deacetylase Hst1p controls biosynthesis and cellular NAD+ levels in Saccharomyces cerevisiae. Mol. Cell. Biol. 23, 7044–7054 (2003).
Hirao, M. et al. Identification of selective inhibitors of NAD+-dependent deacetylases using phenotypic screens in yeast. J. Biol. Chem. 278, 52773–52782 (2003).
Posakony, J. et al. Inhibitors of Sir2: evaluation of splitomicin analogues. J. Med. Chem. (in the press).
Peltomaki, P. Deficient DNA mismatch repair: a common etiologic factor for colon cancer. Hum. Mol. Genet. 10, 735–740 (2001).
Esteller, M. Cancer epigenetics: DNA methylation and chromatin alterations in human cancer. Adv. Exp. Med. Biol. 532, 39–49 (2003).
Weinberg, R. A. The retinoblastoma protein and cell cycle control. Cell 81, 323–330 (1995).
Torrance, C. J. et al. Use of isogenic human cancer cells for high-throughput screening and drug discovery. Nature Biotechnol. 19, 940–945 (2001).
Dunstan, H. M. et al. Cell-based assays for identification of novel double-strand break-inducing agents. J. Natl Cancer Inst. 94, 88–94 (2002).
Cahill, D. P. et al. Mutations of mitotic checkpoint genes in human cancers. Nature 392, 300–303 (1998).
Wassmann, K. & Benezra, R. Mitotic checkpoints: from yeast to cancer. Curr. Opin. Genet. Dev. 11, 83–90 (2001).
Hoyt, M. A., Totis, L. & Roberts, B. T. S. cerevisiae genes required for cell cycle arrest in response to loss of microtubule function. Cell 66, 507–517 (1991).
Griffith, E. C., Licitra, E. J. & Liu, J. O. Yeast three-hybrid system for detecting ligand-receptor interactions. Methods Enzymol. 328, 89–103 (2000).
Hughes, T. R. et al. Functional discovery via a compendium of expression profiles. Cell 102, 109–126 (2000).
Towbin, H. et al. Proteomics-based target identification: bengamides as a new class of methionine aminopeptidase inhibitors. J. Biol. Chem. 278, 52964–52971 (2003).
Momparler, R. L. Cancer epigenetics. Oncogene 22, 6479–6483 (2003).
Thiagalingam, S. et al. Histone deacetylases: unique players in shaping the epigenetic histone code. Ann. NY Acad. Sci. 983, 84–100 (2003).
Luo, J. et al. Negative control of p53 by Sir2α promotes cell survival under stress. Cell 107, 137–148 (2001).
Bereshchenko, O. R. et al. Acetylation inactivates the transcriptional repressor BCL6. Nature Genet. 32, 606–613 (2002).
Frye, R. 'SIRT8' expressed in thyroid cancer is actually SIRT7. Br. J. Cancer 87, 1479 (2002).
Panagopoulos, I. et al. Acute myeloid leukemia with inv(8)(p11q13). Leuk. Lymphoma 39, 651–656 (2000).
Emerling, B. M. et al. MLL5, a homolog of Drosophila trithorax located within a segment of chromosome band 7q22 implicated in myeloid leukemia. Oncogene 21, 4849–4854 (2002).
Varambally, S. et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624–629 (2002).
Keats, J. J. et al. In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression. Blood 101, 1520–1529 (2003).
Feng, Q. et al. Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain. Curr. Biol. 12, 1052–1058 (2002).
van Leeuwen, F. et al. Dot1p modulates silencing in yeast by methylation of the nucleosome core. Cell 109, 745–756 (2002).
Acknowledgements
The authors wish to thank the members of the Simon group for helpful comments and members of the National Cancer Institute's Developmental Therapeutics Program for support in the NCI yeast screen.
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Simon, J., Bedalov, A. Yeast as a model system for anticancer drug discovery. Nat Rev Cancer 4, 481–487 (2004). https://doi.org/10.1038/nrc1372
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DOI: https://doi.org/10.1038/nrc1372
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