ZFIN ID: ZDB-PUB-051219-1
Small molecules that delay S phase suppress a zebrafish bmyb mutant
Stern, H.M., Murphey, R.D., Shepard, J.L., Amatruda, J.F., Straub, C., Pfaff, K.L., Weber, G., Tallarico, J.A., King, R.W. and Zon, L.I.
Date: 2005
Source: Nature Chemical Biology   1(7): 366-370 (Journal)
Registered Authors: Amatruda, James F., Pfaff, Kathleen, Shepard, Jennifer, Stern, Howard, Zon, Leonard I.
Keywords: none
MeSH Terms:
  • Adamantane/analogs & derivatives*
  • Adamantane/chemistry
  • Adamantane/pharmacology
  • Animals
  • Cell Cycle/drug effects
  • Cell Cycle/physiology
  • Cyclin B/drug effects
  • Cyclin B/genetics
  • Cyclin B1
  • Gene Expression Regulation, Developmental/drug effects
  • Mitosis/drug effects
  • Mutation*
  • Phenotype
  • Proto-Oncogene Proteins c-myb/genetics*
  • Proto-Oncogene Proteins c-myb/metabolism
  • Pyridines/chemistry
  • Pyridines/pharmacology*
  • RNA, Messenger/drug effects
  • RNA, Messenger/genetics
  • S Phase/drug effects
  • S Phase/genetics*
  • Zebrafish/embryology
  • Zebrafish/genetics*
  • Zebrafish/growth & development
PubMed: 16372403 Full text @ Nat. Chem. Biol.
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 approx16,000 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.