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Prepublished online as a Blood First Edition Paper on October 10, 2002; DOI 10.1182/blood-2002-05-1517.
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Blood, 1 March 2003, Vol. 101, No. 5, pp. 1769-1776
HEMATOPOIESIS
Enforced expression of CUL-4A interferes with
granulocytic differentiation and exit from the cell
cycle
Binghui Li,
Feng-Chun Yang,
D. Wade Clapp, and
Kristin T. Chun
From the Herman B Wells Center for Pediatric Research,
Indiana University School of Medicine, Indianapolis; the Department of
Pediatrics, Indiana University School of Medicine, Indianapolis; the
Department of Biochemistry and Molecular Biology, Indiana University
School of Medicine, Indianapolis; and the Department of Microbiology
and Immunology, Indiana University School of Medicine, Indianapolis.
The cullin family of proteins is involved in the ubiquitin-mediated
degradation of cell cycle regulators. Relatively little is known about
the function of the CUL-4A cullin, but its overexpression in breast cancer suggests CUL-4A might also regulate the
cell cycle. In addition, since other cullins are required for normal development, we hypothesized that CUL-4A is involved in
regulating cell cycle progression during differentiation. We observed
that CUL-4A mRNA and protein levels decline 2.5-fold during
the differentiation of PLB-985 myeloid cells into granulocytes. To
examine the significance of this observation, we overexpressed
CUL-4A in these cells and found that modest (< 2-fold),
enforced expression of CUL-4A attenuates terminal
granulocytic differentiation and instead promotes proliferation. This
overexpression similarly affects the differentiation of
these cells into macrophages. We recently reported that nearly one half of CUL-4A+/ mice are nonviable, and in this
report, we show that the viable heterozygous mice, which have reduced
CUL-4A expression, have dramatically fewer erythroid and
multipotential progenitors than normal controls. Together these results
indicate that appropriate CUL-4A expression is essential
for embryonic development and for cell cycle regulation during
granulocytic differentiation and suggest this gene plays a broader role
in hematopoiesis. Since enforced CUL-4A expression does not
alter the cell cycle distribution of uninduced cells but dramatically
increases the proportion of induced cells that remains in S-phase and
reduces the proportion that accumulates in
G0/G1, our results show that this
CUL-4A regulatory function is interconnected with
differentiation, a novel finding for mammalian cullins.
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