Deregulated E2f-2 underlies cell cycle and maturation defects in retinoblastoma null erythroblasts.
By assessing the contribution of deregulated E2F activity to erythroid defects in Rb null mice, we have identified E2f-2 as being upregulated in end-stage red cells, where we show it is the major pRb-associated E2f and the predominant E2f detected at key target gene promoters. Consistent with its expression pattern, E2f-2 loss restored terminal erythroid maturation to Rb null red cells, including the ability to undergo enucleation. Deletion of E2f-2 also extended the life span of Rb null mice despite persistent defects in placental development, indicating that deregulated E2f-2 activity in differentiating erythroblasts contributes to the premature lethality of Rb null mice. We show that the aberrant entry of Rb null erythroblasts into S phase at times in differentiation when wild-type erythroblasts are exiting the cell cycle is inhibited by E2f-2 deletion. E2f-2 loss induced cell cycle arrest in both wild-type and Rb null erythroblasts and was associated with increased DNA double-strand breaks. These results implicate deregulated E2f-2 in the cell cycle defects observed in Rb null erythroblasts and reveal a novel role for E2f-2 during terminal red blood cell differentiation. The identification of a tissue-restricted role for E2f-2 in erythropoiesis highlights the nonredundant nature of E2f transcription factor activities in cell growth and differentiation.
Dirlam
Alexandra
A
Ben May Department for Cancer Research, Gordon Center for Integrative Sciences, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA.
Spike
Benjamin T
BT
Macleod
Kay F
KF
D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D004249:DNA Damage; D050703:E2F2 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004900:Erythroblasts / Q000166:cytology* / Q000473:pathology*; D004912:Erythrocytes / Q000166:cytology; D005260:Female; D005328:Fetal Viability; D008136:Longevity; D051379:Mice; D008938:Mitosis; D010641:Phenotype; D010920:Placenta / Q000166:cytology; D016160:Retinoblastoma Protein / Q000172:deficiency*; D016196:S Phase; D015854:Up-Regulation / Q000235:genetics
D050703:E2F2 Transcription Factor; D016160:Retinoblastoma Protein