Letter abstract
Nature Chemical Biology 1, 366 - 370 (2005)
Published online: 13 November 2005 | doi:10.1038/nchembio749
Small molecules that delay S phase suppress a zebrafish bmyb mutant
Howard M Stern1,2,4, Ryan D Murphey2,4, Jennifer L Shepard2, James F Amatruda2, Christian T Straub2, Kathleen L Pfaff2, Gerhard Weber2, John A Tallarico3, Randall W King3 & Leonard I Zon2
Bmyb is a ubiquitously expressed transcription factor involved in cellular proliferation and cancer1, 2, 3, 4. Loss of bmyb function in the zebrafish mutant crash&burn (crb) results in decreased cyclin B1 expression, mitotic arrest and genome instability5. 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 
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.
- Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA.
- Stem Cell Program and Division of Hematology and Oncology, Children's Hospital, Dana-Farber Cancer Institute, Howard Hughes Medical Institute and Harvard Medical School, 1 Blackfan Circle, Boston, Massachusetts 02115, USA.
- Institute of Chemistry and Cell Biology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA.
- These authors contributed equally to this work.
Correspondence to: Leonard I Zon2 e-mail: zon@enders.tch.harvard.edu
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
NEWS AND VIEWS
Small molecules thwart crash and burnNature Chemical Biology News and Views (01 Dec 2005)
RESEARCH
Haemoglobin switching in human embryos: asynchrony of ζ → α and ε → γ-globin switches in primitive and definitive erythropoietic lineageNature Letters to Editor (17 Jan 1985)
Plx1 is required for chromosomal DNA replication under stressful conditionsThe EMBO Journal Article (19 Mar 2008)
Impaired DNA damage checkpoint response in MIF-deficient miceThe EMBO Journal Article (21 Feb 2007)
See all 6 matches for Research
