Small molecules that delay S phase suppress a zebrafish bmyb 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

138 Citations (Scopus)

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 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.

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

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Cyclin B1
Zebrafish
S Phase
Mitosis
Cell Cycle
Embryonic Structures
Aphidicolin
Nucleic Acid Synthesis Inhibitors
Ataxia Telangiectasia
Cell Cycle Proteins
Hydroxyurea
Genomic Instability
Cell Cycle Checkpoints
Libraries
Transcription Factors
Phosphotransferases
Cell Proliferation
Phenotype
Messenger RNA
Neoplasms

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Stern, H. M., Murphey, R. D., Shepard, J. L., Amatruda, J. F., Straub, C. T., Pfaff, K. L., ... Zon, L. I. (2005). Small molecules that delay S phase suppress a zebrafish bmyb mutant. Nature chemical biology., 1(7), 366-370.

Small molecules that delay S phase suppress a zebrafish bmyb mutant. / Stern, Howard M.; Murphey, Ryan D.; Shepard, Jennifer L.; Amatruda, James F.; Straub, Christian T.; Pfaff, Kathleen L.; Weber, Gerhard; Tallarico, John A.; King, Randall W.; Zon, Leonard I.

In: Nature chemical biology., Vol. 1, No. 7, 12.2005, p. 366-370.

Research output: Contribution to journalArticle

Stern, HM, Murphey, RD, Shepard, JL, Amatruda, JF, Straub, CT, Pfaff, KL, Weber, G, Tallarico, JA, King, RW & Zon, LI 2005, 'Small molecules that delay S phase suppress a zebrafish bmyb mutant.', Nature chemical biology., vol. 1, no. 7, pp. 366-370.
Stern HM, Murphey RD, Shepard JL, Amatruda JF, Straub CT, Pfaff KL et al. Small molecules that delay S phase suppress a zebrafish bmyb mutant. Nature chemical biology. 2005 Dec;1(7):366-370.
Stern, Howard M. ; Murphey, Ryan D. ; Shepard, Jennifer L. ; Amatruda, James F. ; Straub, Christian T. ; Pfaff, Kathleen L. ; Weber, Gerhard ; Tallarico, John A. ; King, Randall W. ; Zon, Leonard I. / Small molecules that delay S phase suppress a zebrafish bmyb mutant. In: Nature chemical biology. 2005 ; Vol. 1, No. 7. pp. 366-370.
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