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Prepublished online as a Blood First Edition Paper on October 10, 2002; DOI 10.1182/blood-2002-05-1517.
Submitted May 23, 2002
Accepted October 3, 2002
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*
Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN, USA
Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, IN, USA
Department of Microbiology and Immunology, Indiana University, Indianapolis, IN, USA
* Corresponding author; email: kchun{at}iupui.edu.
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 (less than 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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