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Cell cycle inhibition mediated by the outer surface of the C/EBPα basic region is required but not sufficient for granulopoiesis

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Abstract

CCAAT/enhancer binding protein α (C/EBPα) transactivates target genes dependent upon DNA binding via its basic region-leucine zipper domain and slows G1 progression by interaction with E2F, cdk2, or cdk4. E2F interacts with the non-DNA-binding surface of the C/EBPα basic region and C/EBPα residues 1–70 are required for repressing E2F targets, while cdk2 and cdk4 bind residues 177–191. C/EBPα-ER induces the 32D cl3 myeloblast cell line to differentiate to granulocytes. C/EBPα-ER variants incapable of binding DNA slowed G1, but did not induce early or late granulopoiesis, indicating that cell cycle inhibition as mediated by C/EBPα is not sufficient for differentiation. C/EBPα-ER variants lacking residues 11–70 or residues 11–70 and 178–200 both slowed the G1 to S transition. C/EBPα(GZ)-ER, containing the GCN4 rather than the C/EBPα leucine zipper, also slowed G1. In contrast, C/EBPα(BRM2)-ER, carrying mutations in the outer surface of the basic region required for interaction with E2F, did not slow G1. C/EBPα(BRM2)-ER induced early markers of granulopoiesis much less efficiently than C/EBPα-ER and did not direct terminal maturation. Inhibition of G1 progression using mimosine increased induction of late markers by G-CSF. Thus, both DNA binding and cell cycle arrest, mediated by opposite surfaces of the C/EBPα basic region, are required for granulopoiesis.

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Acknowledgements

This work was supported by National Institutes of Health Grants R01 HL62274 and HL62274 to ADF. ADF is a Leukemia and Lymphoma Society Scholar and is also supported by the Children's Cancer Foundation.

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Authors and Affiliations

  1. Division of Pediatric Oncology, Johns Hopkins University, Baltimore, 21231, MD, USA

    Qian-Fei Wang, Rebecca Cleaves, Tanawan Kummalue & Alan D Friedman

  2. European Molecular Biology Laboratory, Monterotondo-Scalo, 00016, Italy

    Claus Nerlov

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  1. Qian-Fei Wang
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  2. Rebecca Cleaves
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  3. Tanawan Kummalue
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  4. Claus Nerlov
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  5. Alan D Friedman
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Correspondence to Alan D Friedman.

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Wang, QF., Cleaves, R., Kummalue, T. et al. Cell cycle inhibition mediated by the outer surface of the C/EBPα basic region is required but not sufficient for granulopoiesis. Oncogene 22, 2548–2557 (2003). https://doi.org/10.1038/sj.onc.1206360

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