Role of erythropoietin receptor signaling in Friend virus-induced erythroblastosis and polycythemia.
Friend virus is an acutely oncogenic retrovirus that causes erythroblastosis and polycythemia in mice. Previous studies suggested that the Friend virus oncoprotein, gp55, constitutively activates the erythropoietin receptor (EPOR), causing uncontrolled erythroid proliferation. Those studies showed that gp55 confers growth factor independence on an interleukin-3 (IL-3)-dependent cell line (Ba/F3) when the EPOR is coexpressed. Subsequently, we showed that a truncated form of the stem-cell kinase receptor (sf-STK) is required for susceptibility to Friend disease. Given the requirement for sf-STK, we sought to establish the in vivo significance of gp55-mediated activation of the EPOR. We found that the cytoplasmic tyrosine residues of the EPOR, and signal transducer and activator of transcription-5 (STAT5), which acts through these sites, are not required for Friend virus-induced erythroblastosis. The EPOR itself was required for the development of erythroblastosis but not for gp55-mediated erythroid proliferation. Interestingly, the murine EPOR, which is required for gp55-mediated Ba/F3-cell proliferation, was dispensable for erythroblastosis in vivo. Finally, gp55-mediated activation of the EPOR and STAT5 are required for Friend virus-induced polycythemia. These results suggest that Friend virus activates both sf-STK and the EPOR to cause deregulated erythroid proliferation and differentiation.
Zhang
Ji
J
Department of Biochemistry, St Jude Children's Research Hospital, 332 North Lauderdale St, Memphis, TN 38105-2794, USA.
Randall
Mindy S
MS
Loyd
Melanie R
MR
Li
Weimin
W
Schweers
Rachel L
RL
Persons
Derek A
DA
Rehg
Jerold E
JE
Noguchi
Constance T
CT
Ihle
James N
JN
Ney
Paul A
PA
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002472:Cell Transformation, Viral; D004900:Erythroblasts / Q000473:pathology / Q000821:virology; D005622:Friend murine leukemia virus / Q000472:pathogenicity*; D007942:Leukemia, Experimental / Q000209:etiology / Q000473:pathology / Q000821:virology*; D051379:Mice; D018345:Mice, Knockout; D011086:Polycythemia / Q000821:virology*; D017467:Receptors, Erythropoietin / Q000378:metabolism / Q000502:physiology*; D012192:Retroviridae Infections; D050799:STAT5 Transcription Factor / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014412:Tumor Virus Infections; D014759:Viral Envelope Proteins / Q000502:physiology*
D017467:Receptors, Erythropoietin; D050799:STAT5 Transcription Factor; D014759:Viral Envelope Proteins