Spi-1 and mutant p53 regulate different aspects of the proliferation and differentiation control of primary erythroid progenitors.
The emergence of leukemic cells in Friend virus complex-induced erythroleukemia is associated with two recurrent genetic alterations, namely the inactivation of the p53 tumor suppressor gene and the overexpression of Spi-1, a member of the Ets family of transcriptional regulators. In order to determine the role of these genetic alterations on the proliferation and differentiation control of erythroblasts, we expressed Spi-1 and the temperature sensitive mutant p53(V135A) in avian primary erythroid progenitors. We show that enforced expression of Spi-1 in erythroblasts obtained from bone marrow cells by expression of the ts-Sea tyrosine kinase inhibits the execution of the differentiation program normally induced in these cells in response to Epo and insulin and following inactivation of ts-Sea function. In contrast, overexpression of p53(V135A) is without effect on the ability of these cells to differentiate into erythrocytes. However, expression of p53(V135A) in erythroid progenitors obtained from bone marrow cells in the presence of SCF, TGF alpha and estradiol, was found to relieve these cells from their absolute TGF alpha requirement for long term proliferation. This phenotype is dependent upon the expression of the mutant form of p53(V135A) as it is not observed at a temperature at which p53(V135A) regains wild type p53 function. Our results show that each of the genetic alterations which characterize Friend erythroleukemic cells affect in a distinct manner the proliferation and differentiation control of primary erythroid progenitors.
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics*; D002455:Cell Division / Q000235:genetics*; D002478:Cells, Cultured; D002645:Chickens; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics*; D015672:Erythroid Precursor Cells / Q000166:cytology*; D004958:Estradiol / Q000494:pharmacology; D016158:Genes, p53; D008969:Molecular Sequence Data; D009154:Mutation; D015682:Retroviridae Proteins, Oncogenic; D019089:Stem Cell Factor / Q000494:pharmacology; D016211:Transforming Growth Factor alpha / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D004268:DNA-Binding Proteins; D015682:Retroviridae Proteins, Oncogenic; D019089:Stem Cell Factor; D016211:Transforming Growth Factor alpha; C062022:v-Spi-1 protein, Friend spleen focus-forming virus; D004958:Estradiol