The Friend of GATA protein U-shaped functions as a hematopoietic tumor suppressor in Drosophila.
Drosophila has emerged as an important model system to discover and analyze genes controlling hematopoiesis. One regulatory network known to control hemocyte differentiation is the Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) signal-transduction pathway. A constitutive activation mutation of the Janus kinase Hopscotch (hopscotch(Tumorous-lethal); hop(Tum-l)) results in a leukemia-like over-proliferation of hemocytes and copious differentiation of lamellocytes during larval stages. Here we show that the Friend of GATA (FOG) protein U-shaped (Ush) is expressed in circulating and lymph gland hemocytes, where it plays a critical role in controlling blood cell proliferation and differentiation. Our findings demonstrate that a reduction in ush function results in hematopoietic phenotypes strikingly similar to those observed in hop(Tum-l) animals. These include lymph gland hypertrophy, increased circulating hemocyte concentration, and abundant production of lamellocytes. Forced expression of N-terminal truncated versions of Ush likewise leads to larvae with severe hematopoietic anomalies. In contrast, expression of wild-type Ush results in a strong suppression of hop(Tum-l) phenotypes. Taken together, our findings demonstrate that U-shaped acts to control larval hemocyte proliferation and suppress lamellocyte differentiation, likely regulating hematopoietic events downstream of Hop kinase activity. Such functions appear to be facilitated through Ush interaction with the hematopoietic GATA factor Serpent (Srp).
Sorrentino
Richard Paul
RP
Department of Biochemistry and Molecular Biology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Tokusumi
Tsuyoshi
T
Schulz
Robert A
RA
D000818:Animals; D030801:Animals, Genetically Modified; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000033:anatomy & histology / Q000502:physiology*; D050980:GATA Transcription Factors / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D016147:Genes, Tumor Suppressor; D006413:Hematopoietic System / Q000502:physiology*; D006434:Hemocytes / Q000166:cytology / Q000502:physiology*; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism*; D007814:Larva / Q000166:cytology / Q000502:physiology; D010641:Phenotype; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes
D029721:Drosophila Proteins; C508614:FOG protein, Drosophila; D050980:GATA Transcription Factors; D014157:Transcription Factors; C103965:srp protein, Drosophila; C109258:ush protein, Drosophila; D053612:Janus Kinases; C085845:hop protein, Drosophila