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Molecular and Cellular Biology, April 2002, p. 2663-2672, Vol. 22, No. 8
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.8.2663-2672.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Mutant Mouse Models Reveal the Relative Roles of E2F1 and E2F3 In Vivo

Jennifer E. Cloud,1 Catherine Rogers,1 Tammi L. Reza,1 Ulrike Ziebold,1 James R. Stone,2 Michael H. Picard,3 Alicia M. Caron,1 Roderick T. Bronson,4 and Jacqueline A. Lees1*

Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139,1 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115,2 Cardiology Division and Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 ,3 Department of Pathology, Tufts University School of Veterinary Medicine, Boston, Massachusetts 021114

Received 21 November 2001/ Returned for modification 21 December 2001/ Accepted 18 January 2002

The E2F1, -2, and -3 transcription factors are key downstream targets of the retinoblastoma protein (pRB) tumor suppressor that drive expression of proliferation-associated genes. Here we use mutant mouse strains to investigate E2F3's role in vivo. We show that E2F3 is essential for embryonic viability in the pure 129/Sv background but the presence of C57BL/6 alleles yields some adult survivors. Although growth retarded, surviving E2f3-/- animals are initially healthy. However, they die prematurely, exhibiting no obvious tumor phenotype but with the typical signs of congestive heart failure. The defects are completely distinct from those arising in E2f1 mutant mice (S. J. Field et al., Cell 85:549-561; 1996; L. Yamasaki et al., Cell 85:537-548, 1996), supporting the prevailing view that these E2Fs must have some unique biological functions in vivo. To test this model, we examined the phenotypes of E2f1 E2f3 compound mutant mice. Almost all of the developmental and age-related defects arising in the individual E2f1 or E2f3 mice were exacerbated by the mutation of the other E2f. Thus, E2F1 and E2F3 appear to play critical, overlapping roles in the development and maintenance of a variety of tissues. Importantly, this study did identify one major difference in the properties of E2F1 and E2F3: either alone or in combination with E2F1 loss, E2f3 mutation did not increase the incidence of tumor formation. These data strongly suggest that tumor suppression is a specific property of E2F1 and not E2F3.

* Corresponding author. Mailing address: Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139. Phone: (617) 252-1972. Fax: (617) 253-9863. E-mail: jalees{at}mit.edu.

Molecular and Cellular Biology, April 2002, p. 2663-2672, Vol. 22, No. 8
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.8.2663-2672.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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