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Blood, 1 August 2006, Vol. 108, No. 3, pp. 886-895.
Prepublished online as a Blood First Edition Paper on April 4, 2006; DOI 10.1182/blood-2005-09-008656.
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Submitted September 15, 2005
Accepted March 15, 2006
E2f4 regulates fetal erythropoiesis through the
promotion of cellular proliferation
Kathryn M Kinross, Allison J Clark, Rosa M Iazzolino, and Patrick Orson Humbert*
Cell Cycle and Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia
* Corresponding author; email: patrick.humbert{at}petermac.org.
The E2F proteins are major regulators of the
transcriptional program required to coordinate cell
cycle progression and exit. In particular, E2f4 has
been proposed to be the principal family member
responsible for the regulation of cell cycle exit
chiefly through its transcriptional repressive
properties. We have previously shown that E2f4-/- mice
display a marked macrocytic anemia implicating E2f4 in
the regulation of erythropoiesis. However, these studies
could not distinguish whether E2f4 was required for
differentiation, survival or proliferation control.
Here we describe a novel function for E2f4 in the
promotion of erythroid proliferation. We show that loss
of E2f4 results in impaired expansion of the fetal
erythroid compartment in vivo which is associated with
impaired cell cycle progression and decreased erythroid
proliferation. Consistent with these observations, cDNA
microarray analysis reveals cell cycle control genes as
one of the major class of genes downregulated in E2f4-/-
FLs and we provide evidence that E2f4 may directly
regulate the transcriptional expression of a number of
these genes. We conclude that the macrocytic anemia of
E2f4-/- mice results primarily from impaired cellular
proliferation and that the major role of E2f4 in fetal
erythropoiesis is to promote cell cycle progression and
cellular proliferation.
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