Enforced expression of CUL-4A interferes with granulocytic differentiation and exit from the cell cycle.
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.
Li
Binghui
B
Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202 USA.
Yang
Feng-Chun
FC
Clapp
D Wade
DW
Chun
Kristin T
KT
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D044842:Cullin Proteins; D018076:DNA, Complementary / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D016259:Genes, myc; D005838:Genotype; D006098:Granulocytes / Q000166:cytology*; D006410:Hematopoiesis / Q000502:physiology*; D008264:Macrophages / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000502:physiology; D050717:Retinoblastoma-Like Protein p130
C114234:CUL4A protein, human; C491940:Cul4a protein, mouse; D044842:Cullin Proteins; D018076:DNA, Complementary; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D011993:Recombinant Fusion Proteins; D050717:Retinoblastoma-Like Protein p130