Small molecules that delay S phase suppress a zebrafish bmyb mutant
| Autor: | Howard M. Stern, Christian T. Straub, Leonard I. Zon, James F. Amatruda, Gerhard J. Weber, Ryan D. Murphey, John A. Tallarico, Kathleen L. Pfaff, Randall W. King, Jennifer L. Shepard |
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| Rok vydání: | 2005 |
| Předmět: |
Genome instability
Aphidicolin Pyridines Mitosis Adamantane Cyclin B S Phase Proto-Oncogene Proteins c-myb chemistry.chemical_compound Animals RNA Messenger Cyclin B1 Molecular Biology Zebrafish Gene knockdown biology Kinase Cell Cycle Gene Expression Regulation Developmental Cell Biology Cell cycle biology.organism_classification Cell biology Phenotype chemistry Mutation |
| Zdroj: | Nature Chemical Biology. 1:366-370 |
| ISSN: | 1552-4469 1552-4450 |
| Popis: | Bmyb is a ubiquitously expressed transcription factor involved in cellular proliferation and cancer. Loss of bmyb function in the zebrafish mutant crash&burn (crb) results in decreased cyclin B1 expression, mitotic arrest and genome instability. These phenotypic observations in crb mutants could be attributed to the decreased expression of cyclin B1, a cell-cycle regulatory protein that is responsible for driving cell progression from G2 through mitosis. To identify small molecules that interact with the bmyb pathway, we developed an embryo-based suppressor screening strategy. In 16 weeks we screened a diverse approximately 16,000 compound library, and discovered one previously unknown compound, persynthamide (psy, 1), that suppressed bmyb-dependent mitotic defects. Psy-treated embryos showed an S-phase delay, and knockdown of the cell-cycle checkpoint regulator ataxia telangiectasia--and Rad-related kinase (ATR) abrogated the suppression of crb. The DNA synthesis inhibitors aphidicolin (2) and hydroxyurea (3) also suppressed crb. S-phase inhibition upregulated cyclin B1 mRNA, promoting the progression of cells through mitosis. Our study demonstrates that chemical suppressor screening in zebrafish can identify compounds with cell-cycle activity and can be used to identify pathways that interact with specific cell-cycle phenotypes. |
| Databáze: | OpenAIRE |
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