Document Detail


Constitutive activation of zebrafish Stat5 expands hematopoietic cell populations in vivo.
MedLine Citation:
PMID:  16459186     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: Constitutive activation of Stat5 has been observed in a variety of malignancies, particularly myeloid leukemias. To directly investigate the in vivo consequences of Stat5 perturbation, we expressed constitutively active forms in zebrafish. METHODS: We generated mutants of the zebrafish stat5.1 protein (N646H, H298R/N714F, and N714F) based on previously identified constitutively active mutants of murine Stat5a. The in vitro properties of these mutants were determined using phosphorylation-specific antibodies and luciferase reporter assays, and their in vivo effects were analyzed through microinjection of zebrafish embryos. RESULTS: Two of these stat5.1 mutants (N646H and H298R/N714F) showed increased tyrosine phosphorylation and transactivation activity compared to the wild-type protein. Expression of either mutant led to a range of hematological perturbations, which were more pronounced for the H298R/N714F mutant. Interestingly, expression of wild-type also produced generally similar phenotypes. Further analysis showed that expression of the H298R/N714F mutant led to increased numbers of early and late myeloid cells, erythrocytes, and B cells. Some nonhematopoietic developmental perturbations were also observed, but these were equally prominent with wild-type or mutant forms. CONCLUSION: These data implicate Stat5 activity as a direct critical regulator of hematological cell proliferation, suggesting a causal role for constitutively-active Stat5 in the etiology of hematological malignancies.
Authors:
Rowena S Lewis; Sarah E M Stephenson; Alister C Ward
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Publication Detail:
Type:  Comparative Study; In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Experimental hematology     Volume:  34     ISSN:  0301-472X     ISO Abbreviation:  Exp. Hematol.     Publication Date:  2006 Feb 
Date Detail:
Created Date:  2006-02-06     Completed Date:  2006-03-23     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0402313     Medline TA:  Exp Hematol     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  179-87     Citation Subset:  IM    
Affiliation:
Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin University, Burwood, Victoria, Australia.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Substitution
Animals
Cell Line
Cell Lineage / physiology
Cell Proliferation / drug effects
Hematologic Diseases / genetics*,  pathology
Hematopoietic Stem Cells / cytology,  drug effects,  metabolism*
Humans
Mutagenesis, Site-Directed
Mutation
Phosphorylation
STAT5 Transcription Factor / genetics,  pharmacology,  physiology*
Tyrosine / drug effects,  metabolism
Zebrafish
Zebrafish Proteins / genetics,  pharmacology,  physiology*
Chemical
Reg. No./Substance:
0/STAT5 Transcription Factor; 0/Zebrafish Proteins; 0/stat5.1 protein, zebrafish; 55520-40-6/Tyrosine

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