Peptide inhibitors of the anaphase promoting-complex that cause sensitivity to microtubule poison
| Autor: | Yu-Ting Chu, Chia-Jung Lin, Hsin-Yu Chen, Ting-Chun Chen, Scott C. Schuyler, Yi-Shan Ding, Ting-Wei Liao, Lin-Ing Wang, Anna Huang, Vivien Cheng, Wei-Wei Tsai, Jia-Hua Jhuo, Yueh-Fu Olivia Wu, Louis Liao |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Mad2 lcsh:Medicine Yeast and Fungal Models Toxicology Pathology and Laboratory Medicine Microtubules Cdh1 Proteins Neoplasms Mad2 Proteins Medicine and Health Sciences Toxins Cell Cycle and Cell Division Enzyme Inhibitors lcsh:Science Cytoskeleton Multidisciplinary biology Chemistry Eukaryota Tubulin Modulators Cell biology Phenotypes Securin Experimental Organism Systems Cell Processes Amino Acid Analysis Cellular Structures and Organelles Research Article Saccharomyces cerevisiae Proteins Cdc20 Proteins Cognitive Neuroscience Saccharomyces cerevisiae Toxic Agents Mitosis Antineoplastic Agents CDC20 Research and Analysis Methods Anaphase-Promoting Complex-Cyclosome 03 medical and health sciences Saccharomyces Model Organisms Microtubule Genetics Reaction Time Humans Protein Interaction Domains and Motifs Molecular Biology Techniques Molecular Biology Enzyme Assays Molecular Biology Assays and Analysis Techniques lcsh:R Organisms Fungi Biology and Life Sciences Cell Biology biology.organism_classification Yeast 030104 developmental biology Drug Resistance Neoplasm Cognitive Science lcsh:Q Anaphase-promoting complex Peptides Neuroscience |
| Zdroj: | PLoS ONE PLoS ONE, Vol 13, Iss 6, p e0198930 (2018) |
| ISSN: | 1932-6203 |
| Popis: | There is an interest in identifying Anaphase Promoting-Complex/Cyclosome (APC/C) inhibitors that lead to sensitivity to microtubule poisons as a strategy for targeting cancer cells. Using budding yeast Saccharomyces cerevisiae, peptides derived from the Mitotic Arrest Deficient 2 (Mad2)-binding motif of Cell Division Cycle 20 (Cdc20) were observed to inhibit both Cdc20- and CDC20 Homology 1 (Cdh1)-dependent APC/C activity. Over expression of peptides in vivo led to sensitivity to a microtubule poison and, in a recovery from a microtubule poison arrest, delayed degradation of yeast Securin protein Precocious Dissociation of Sisters 1 (Pds1). Peptides with mutations in the Cdc20 activating KILR-motif still bound APC/C, but lost the ability to inhibit APC/C in vitro and lost the ability to induce sensitivity to a microtubule poison in vivo. Thus, an APC/C binding and activation motif that promotes mitotic progression, namely the Cdc20 KILR-motif, can also function as an APC/C inhibitor when present in excess. Another activator for mitotic progression after recovery from microtubule poison is p31comet, where a yeast predicted open-reading frame YBR296C-A encoding a 39 amino acid predicted protein was identified by homology to p31comet, and named Tiny Yeast Comet 1 (TYC1). Tyc1 over expression resulted in sensitivity to microtubule poison. Tyc1 inhibited both APC/CCdc20 and APC/CCdh1 activities in vitro and bound to APC/C. A homologous peptide derived from human p31comet bound to and inhibited yeast APC/C demonstrating evolutionary retention of these biochemical activities. Cdc20 Mad2-binding motif peptides and Tyc1 disrupted the ability of the co-factors Cdc20 and Cdh1 to bind to APC/C, and co-over expression of both together in vivo resulted in an increased sensitivity to microtubule poison. We hypothesize that Cdc20 Mad2-binding motif peptides, Tyc1 and human hp31 peptide can serve as novel molecular tools for investigating APC/C inhibition that leads to sensitivity to microtubule poison in vivo. |
| Databáze: | OpenAIRE |
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