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Molecular and Cellular Biology, February 2006, p. 1527-1537, Vol. 26, No. 4
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.4.1527-1537.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

An E2F Binding-Deficient Rb1 Protein Partially Rescues Developmental Defects Associated with Rb1 Nullizygosity

Huifang Sun,^1, Yanjie Chang,^1, Brett Schweers,² Michael A. Dyer,² Xiaojing Zhang,¹ Simon W. Hayward,³ and David W. Goodrich^1*

Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263,¹ Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105,² Departments of Urologic Surgery and Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37235³

Received 31 August 2005/ Returned for modification 8 October 2005/ Accepted 4 December 2005

Rb1 is essential for normal embryonic development, as null mice die in midgestation with widespread unscheduled cell proliferation. Rb1 protein (pRb) mediates cell cycle control by binding E2F transcription factors and repressing expression from E2F-dependent promoters. An increasing amount of evidence suggests that pRb loss also compromises cellular differentiation. Since differentiation is often dependent on cell cycle exit, it is currently unclear whether the effects of pRb on differentiation are an indirect consequence of pRb/E2F-mediated cell cycle control or whether they reflect direct cell-type-specific pRb functions. We have mutated Rb1 in the mouse to express a protein (R654W) specifically deficient in binding E2F1, E2F2, and E2F3. R654W mutant embryos exhibit cell cycle defects the same as those of Rb1 null embryos, reinforcing the importance of the interactions of pRb with E2F1, E2F2, and E2F3 for cell cycle control. However, R654W embryos survive at least 2 days longer than Rb1 null embryos, and increased life span is associated with improved erythrocyte and fetal liver macrophage differentiation. In contrast, R654W pRb does not rescue differentiation defects associated with pRb-deficient retinae. These data indicate that Rb1 makes important cell-type-specific contributions to cellular differentiation that are genetically separable from its general ability to stably bind E2F1, E2F2, and E2F3 and regulate the cell cycle.

Supplemental material for this article may be found at http://mcb.asm.org/.

These authors contributed equally to the work.

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