Constitutive activation of zebrafish Stat5 expands hematopoietic cell populations in vivo.

2.50
Hdl Handle:
http://hdl.handle.net/10146/68415
Title:
Constitutive activation of zebrafish Stat5 expands hematopoietic cell populations in vivo.
Authors:
Lewis, Rowena S.; Stephenson, Sarah E. M.; Ward, Alister C.
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.
Citation:
Exp. Hematol. 2006, 34 (2):179-87
Journal:
Experimental hematology
Issue Date:
Feb-2006
URI:
http://hdl.handle.net/10146/68415
DOI:
10.1016/j.exphem.2005.11.003
PubMed ID:
16459186
Additional Links:
http://linkinghub.elsevier.com/retrieve/pii/S0301-472X(05)00526-6
Type:
Article
Language:
en
Description:
KEYWORDS - 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.
ISSN:
0301-472X
Appears in Collections:
Articles with annotation

Full metadata record

DC FieldValue Language
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.en
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

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