FLI-1 inhibits differentiation and induces proliferation of primary erythroblasts.
Friend virus-induced erythroleukemia involves two members of the ETS family of transcriptional regulators, both activated via proviral insertion in the corresponding loci. Spi-1/PU.1 is expressed in the disease induced by the original Friend virus SFFV(F-MuLV) complex in adult mice. In contrast, FLI-1 is overexpressed in about 75% of the erythroleukemias induced by the F-MuLV helper virus in newborn mice. To analyse the consequences of the enforced expression of FLI-1 on erythroblast differentiation and proliferation and to compare its activity to that of PU.1/Spi-1, we used a heterologous system of avian primary erythroblasts previously described to study the cooperation between Spi-1/PU.1 and the other molecular alterations observed in SFFV-induced disease. FLI-1 was found: (i) to inhibit the apoptotic cell death program normally activated in erythroblasts following Epo deprivation; (ii) to inhibit the terminal differentiation program induced in these cells in response to Epo and; (iii) to induce their proliferation. However, in contrast to Spi-1/PU.1, the effects of FLI-1 on erythroblast, differentiation and proliferation did not require its cooperation with an abnormally activated form of the EpoR. Enhanced survival of FLI-1 expressing erythroblasts correlated with the upregulation of bcl2 expression. FLI-1 also prevented the rapid downregulation of cyclin D2 and D3 expression normally observed during Epo-induced differentiation and delayed the downregulation of several other genes involved in cell cycle or cell proliferation control. Our results show that overexpression of FLI-1 profoundly deregulates the normal balance between differentiation and proliferation in primary erythroblasts. Thus, the activation of FLI-1 expression observed at the onset of F-MuLV-induced erythroleukemia may provide a proliferative advantage to virus infected cells that would otherwise undergo terminal differentiation or cell death.
Pereira
R
R
CNRS UMR146, Institut Curie-Section de Recherche, Centre Universitaire, Orsay, France.
Quang
C T
CT
Lesault
I
I
Dolznig
H
H
Beug
H
H
Ghysdael
J
J
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D002645:Chickens; D056742:Cyclin D2; D056743:Cyclin D3; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology*; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000378:metabolism; D004920:Erythropoiesis / Q000502:physiology*; D005347:Fibroblasts; D005622:Friend murine leukemia virus / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D019254:Genes, bcl-2; D051379:Mice; D008969:Molecular Sequence Data; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D017467:Receptors, Erythropoietin / Q000502:physiology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015534:Trans-Activators / Q000502:physiology*; D014162:Transfection; D000099232:Proto-Oncogene Protein Spi-1
D056742:Cyclin D2; D056743:Cyclin D3; D016213:Cyclins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017467:Receptors, Erythropoietin; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C486196:Ccnd2 protein, mouse; C534697:Ccnd3 protein, mouse; C497426:Fli1 protein, mouse