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Small molecules that delay S phase suppress a zebrafish bmyb mutant
Howard M Stern1, Ryan D Murphey, Jennifer L Shepard
1Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA.
Nature Chemical Biology
|December 24, 2005
Summary
A novel compound, persynthamide, was identified using zebrafish screening to suppress cell cycle defects caused by Bmyb loss. This compound induces an S-phase delay, highlighting a new therapeutic avenue for cell proliferation disorders.
Area of Science:
- Molecular Biology
- Genetics
- Pharmacology
Background:
- Bmyb is a transcription factor crucial for cell proliferation and implicated in cancer.
- Loss of Bmyb function in zebrafish mutants (crash&burn) leads to mitotic arrest and genome instability due to decreased cyclin B1 expression.
Purpose of the Study:
- To identify small molecules that modulate the Bmyb pathway using a zebrafish embryo-based suppressor screen.
- To investigate the mechanism by which identified compounds affect cell-cycle progression.
Main Methods:
- Screened approximately 16,000 compounds in zebrafish embryos to find suppressors of Bmyb-dependent mitotic defects.
- Utilized knockdown of ataxia telangiectasia--and Rad-related kinase (ATR) and treatment with DNA synthesis inhibitors (aphidicolin, hydroxyurea) to analyze compound effects.
- Monitored cyclin B1 mRNA levels and cell-cycle progression (S-phase delay) in treated embryos.
Main Results:
- Discovered persynthamide (psy), a novel compound that suppresses Bmyb-dependent mitotic defects.
- Persynthamide induced an S-phase delay, and its suppressive effect was abrogated by ATR knockdown.
- DNA synthesis inhibitors also suppressed the mutant phenotype, and S-phase inhibition upregulated cyclin B1 mRNA.
Conclusions:
- Chemical suppressor screening in zebrafish is an effective strategy for identifying compounds with cell-cycle activity.
- Persynthamide and S-phase inhibition can rescue Bmyb-loss-induced cell-cycle defects by upregulating cyclin B1.
- This study identifies potential therapeutic targets and compounds for treating disorders of cell proliferation and cancer.