Cul4A targets p27 for degradation and regulates proliferation, cell cycle exit, and differentiation during erythropoiesis
| Autor: | Nan Jia, Reuben Kapur, Binghui Li, Kristin T. Chun |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Heterozygote
Cellular differentiation Immunology Biology Biochemistry Mice Animals Erythropoiesis Progenitor cell Cells Cultured Erythroid Precursor Cells Cell Proliferation Mice Knockout Cell growth Cell Cycle Cell Differentiation Cell Biology Hematology Cell cycle Cullin Proteins Molecular biology Hematopoiesis Cell biology Ubiquitin ligase Erythrocyte maturation biology.protein Fluorouracil CUL4A Cyclin-Dependent Kinase Inhibitor p27 |
| Zdroj: | Blood. 107:4291-4299 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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