Small Molecules that Delay s Phase Suppress a Zebrafish Bmyh Mutant

Howard M. Stern, Ryan D. Murphey, Jennifer L. Shepard, James F. Amatruda, Christian T. Straub, Kathleen L. Pfaff, Gerhard Weber, John A. Tallarico, Randall W. King, Leonard I. Zon

Research output: Contribution to journalArticle

142 Scopus citations

Abstract

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 ∼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.

Original languageEnglish (US)
Pages (from-to)366-370
Number of pages5
JournalNature chemical biology
Volume1
Issue number7
DOIs
StatePublished - Dec 2005

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Small Molecules that Delay s Phase Suppress a Zebrafish Bmyh Mutant'. Together they form a unique fingerprint.

  • Cite this

    Stern, H. M., Murphey, R. D., Shepard, J. L., Amatruda, J. F., Straub, C. T., Pfaff, K. L., Weber, G., Tallarico, J. A., King, R. W., & Zon, L. I. (2005). Small Molecules that Delay s Phase Suppress a Zebrafish Bmyh Mutant. Nature chemical biology, 1(7), 366-370. https://doi.org/10.1038/nchembio749