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Genes & Dev. 22 (4): 463-475

Copyright © 2008 by Cold Spring Harbor Laboratory Press.

Rb intrinsically promotes erythropoiesis by coupling cell cycle exit with mitochondrial biogenesis

Vijay G. Sankaran1,2, Stuart H. Orkin,1,2,3,4,, and Carl R. Walkley1,2

1 Division of Hematology/Oncology, Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA;
2 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;
3 Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA

Abstract: Regulation of the cell cycle is intimately linked to erythroid differentiation, yet how these processes are coupled is not well understood. To gain insight into this coordinate regulation, we examined the role that the retinoblastoma protein (Rb), a central regulator of the cell cycle, plays in erythropoiesis. We found that Rb serves a cell-intrinsic role and its absence causes ineffective erythropoiesis, with a differentiation block at the transition from early to late erythroblasts. Unexpectedly, in addition to a failure to properly exit the cell cycle, mitochondrial biogenesis fails to be up-regulated concomitantly, contributing to this differentiation block. The link between erythropoiesis and mitochondrial function was validated by inhibition of mitochondrial biogenesis. Erythropoiesis in the absence of Rb resembles the human myelodysplastic syndromes, where defects in cell cycle regulation and mitochondrial function frequently occur. Our work demonstrates how these seemingly disparate pathways play a role in coordinately regulating cellular differentiation.

Key Words: Rb • cell cycle • cell differentiation • erythropoiesis • hematopoiesis • mitochondrial biogenesis]

Received for publication October 19, 2007. Accepted for publication December 6, 2007.

4 Corresponding author.

E-MAIL stuart_orkin{at}; FAX (617) 632-4367.

Supplemental material is available at

Article published online ahead of print. Article and publication date are online at

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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