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dc.contributor.authorLewis, Rowena S.
dc.contributor.authorStephenson, Sarah E. M.
dc.contributor.authorWard, Alister C.
dc.date.accessioned2009-05-18T07:06:38Z
dc.date.available2009-05-18T07:06:38Z
dc.date.issued2006-02
dc.identifier.citationExp. Hematol. 2006, 34 (2):179-87en
dc.identifier.issn0301-472X
dc.identifier.pmid16459186
dc.identifier.doi10.1016/j.exphem.2005.11.003
dc.identifier.urihttp://hdl.handle.net/10146/68415
dc.descriptionKEYWORDS - CLASSIFICATION: analysis;Amino Acid Substitution;Animals;Biology;cytology;Cell Line;Cell Lineage;Cell Proliferation;drug effects;etiology;genetics;Hematologic Diseases;Hematopoietic Stem Cells;Humans;metabolism;mechanisms of carcinogenesis;Molecular Biology;Mutagenesis,Site-Directed;Mutation;pathology;pharmacology;physiology;Phosphorylation;Proteins;Research;STAT5 Transcription Factor;Tyrosine;Zebrafish;Zebrafish Proteins.en
dc.description.abstractOBJECTIVE: 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.
dc.language.isoenen
dc.relation.urlhttp://linkinghub.elsevier.com/retrieve/pii/S0301-472X(05)00526-6en
dc.subject.meshAmino Acid Substitution
dc.subject.meshAnimals
dc.subject.meshCell Line
dc.subject.meshCell Lineage
dc.subject.meshCell Proliferation
dc.subject.meshHematologic Diseases
dc.subject.meshHematopoietic Stem Cells
dc.subject.meshHumans
dc.subject.meshMutagenesis, Site-Directed
dc.subject.meshMutation
dc.subject.meshPhosphorylation
dc.subject.meshSTAT5 Transcription Factor
dc.subject.meshTyrosine
dc.subject.meshZebrafish
dc.subject.meshZebrafish Proteins
dc.titleConstitutive activation of zebrafish Stat5 expands hematopoietic cell populations in vivo.en
dc.typeArticleen
dc.identifier.journalExperimental hematologyen
html.description.abstractOBJECTIVE: 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.


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