PUBLICATION
Constitutive activation of zebrafish Stat5 expands hematopoietic cell populations in vivo
- Authors
- Lewis, R.S., Stephenson, S.E., and Ward, A.C.
- ID
- ZDB-PUB-060210-15
- Date
- 2006
- Source
- Experimental hematology 34(2): 179-187 (Journal)
- Registered Authors
- Ward, Alister C.
- Keywords
- none
- MeSH Terms
-
- Amino Acid Substitution
- Animals
- Cell Line
- Cell Lineage/physiology
- Cell Proliferation/drug effects
- Hematologic Diseases/genetics*
- Hematologic Diseases/pathology
- Hematopoietic Stem Cells/cytology
- Hematopoietic Stem Cells/drug effects
- Hematopoietic Stem Cells/metabolism*
- Humans
- In Vitro Techniques
- Mutagenesis, Site-Directed
- Mutation
- Phosphorylation
- STAT5 Transcription Factor/genetics
- STAT5 Transcription Factor/pharmacology
- STAT5 Transcription Factor/physiology*
- Tyrosine/drug effects
- Tyrosine/metabolism
- Zebrafish
- Zebrafish Proteins/genetics
- Zebrafish Proteins/pharmacology
- Zebrafish Proteins/physiology*
- PubMed
- 16459186 Full text @ Exp. Hematol.
Citation
Lewis, R.S., Stephenson, S.E., and Ward, A.C. (2006) Constitutive activation of zebrafish Stat5 expands hematopoietic cell populations in vivo. Experimental hematology. 34(2):179-187.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping