Cul4A targets p27 for degradation and regulates proliferation, cell cycle exit, and differentiation during erythropoiesis.
As erythroid progenitors differentiate into precursors and finally mature red blood cells, lineage-specific genes are induced, and proliferation declines until cell cycle exit. Cul4A encodes a core subunit of a ubiquitin ligase that targets proteins for ubiquitin-mediated degradation, and Cul4A-haploinsufficient mice display hematopoietic dysregulation with fewer multipotential and erythroid-committed progenitors. In this study, stress induced by 5-fluorouracil or phenylhydrazine revealed a delay in the recovery of erythroid progenitors, early precursors, and normal hematocrits in Cul4A(+/-) mice. Conversely, overexpression of Cul4A in a growth factor-dependent, proerythroblast cell line increased proliferation and the proportion of cells in S phase. When these proerythroblasts were induced to terminally differentiate, endogenous Cul4A protein expression declined 3.6-fold. Its enforced expression interfered with erythrocyte maturation and cell cycle exit and, instead, promoted proliferation. Furthermore, p27 normally accumulates during erythroid terminal differentiation, but Cul4A-enforced expression destabilized p27 and attenuated its accumulation. Cul4A and p27 proteins coimmunoprecipitate, indicating that a Cul4A ubiquitin ligase targets p27 for degradation. These findings indicate that a Cul4A ubiquitin ligase positively regulates proliferation by targeting p27 for degradation and that Cul4A down-regulation during terminal erythroid differentiation allows p27 to accumulate and signal cell cycle exit.
Li
Binghui
B
Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Jia
Nan
N
Kapur
Reuben
R
Chun
Kristin T
KT
D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D044842:Cullin Proteins / Q000502:physiology*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D015672:Erythroid Precursor Cells / Q000166:cytology*; D004920:Erythropoiesis; D005472:Fluorouracil / Q000494:pharmacology; D006579:Heterozygote; D051379:Mice; D018345:Mice, Knockout
C491940:Cul4a protein, mouse; D044842:Cullin Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005472:Fluorouracil