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Molecular and Cellular Biology, December 2007, p. 8713-8728, Vol. 27, No. 24
0270-7306/07/$08.00+0     doi:10.1128/MCB.01118-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Deregulated E2f-2 Underlies Cell Cycle and Maturation Defects in Retinoblastoma Null Erythroblasts{triangledown}

Alexandra Dirlam,1,2 Benjamin T. Spike,1,3 and Kay F. Macleod1,2,3*

Ben May Department for Cancer Research, Gordon Center for Integrative Sciences, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637,1 Committee on Immunology, The University of Chicago, Chicago, Illinois,2 Committee on Cancer Biology, The University of Chicago, Chicago, Illinois3

Received 23 June 2007/ Returned for modification 27 July 2007/ Accepted 29 September 2007

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.

* Corresponding author. Mailing address: Ben May Department for Cancer Research, Gordon Center for Integrative Sciences, The University of Chicago, 929 East 57th Street, Chicago, IL 60637. Phone: (773) 834-8309. Fax: (773) 702-4476. E-mail: kmacleod{at}huggins.bsd.uchicago.edu

{triangledown} Published ahead of print on 8 October 2007.

Molecular and Cellular Biology, December 2007, p. 8713-8728, Vol. 27, No. 24
0270-7306/07/$08.00+0     doi:10.1128/MCB.01118-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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