Fbw7-dependent cyclin E regulation ensures terminal maturation of bone marrow erythroid cells by restraining oxidative metabolism

• Published in: Oncogene Vol. 33; no. 24; pp. 3161 - 3171
• Main Authors: Xu, Y, Swartz, K L, Siu, K T, Bhattacharyya, M, Minella, A C
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12-06-2014; Nature Publishing Group
• Subjects: 631/136/232/1473; 631/443/319; 631/67/1990; Analysis; Animal models; Animals; Apoptosis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Blotting, Western; Bone marrow; Bone Marrow Cells - cytology; Bone Marrow Cells - metabolism; Bone Marrow Transplantation; Cdc4 protein; Cell Biology; Cell differentiation; Cell Proliferation; Cell survival; Cyclin E; Cyclin E - metabolism; DNA damage; DNA methylation; Dysplasia; E protein; Enucleation; Erythrocytes; Erythroid cells; Erythroid Cells - metabolism; Erythropoiesis; Evolution; F-Box Proteins - physiology; F-Box-WD Repeat-Containing Protein 7; Flow Cytometry; Gene expression; Gene Expression Profiling; Histone H3; Histones; Human Genetics; Influence; Internal Medicine; Lysine; Medicine; Medicine & Public Health; Metabolism; Mice; Mice, Transgenic; Mitochondria; Mitochondria - metabolism; Myelodysplastic syndrome; Myelodysplastic syndromes; Oligonucleotide Array Sequence Analysis; Oncology; original-article; Oxidative metabolism; p53 Protein; Phenotypes; Phosphorylation; Proteasomes; Reactive oxygen species; Reactive Oxygen Species - metabolism; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Risk factors; RNA, Messenger - genetics; Tumor proteins; Tumor Suppressor Protein p53 - physiology; Ubiquitin-Protein Ligases - physiology; cyclin E; erythropoiesis; Fbw7; reactive oxygen species; p53
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2013.289

The mechanisms that coordinate the final mitotic divisions of terminally differentiated bone marrow (BM) erythroid cells with components of their structural and functional maturation program remain largely undefined. We previously identified phenotypes resembling those found in early-stage myelodysplastic syndromes (MDS), including ineffective erythropoiesis, morphologic dysplasia and BM hyper-cellularity, in a knock-in mouse model in which cyclin E mutations were introduced at its two Cdc4 phosphodegrons (CPDs) to ablate Fbw7-dependent ubiquitination and degradation. Here, we have examined the physiologic consequences of cyclin E dysregulation in BM erythroid cells during terminal maturation
in vivo
. We found that cyclin E protein levels in BM erythroid cells are dynamically regulated in a CPD-dependent manner and that disruption of Fbw7-dependent cyclin E regulation impairs terminal erythroid cell maturation at a discrete stage before enucleation. At this stage of erythroid cell maturation, CPD phosphorylation of cyclin E regulates both cell-cycle arrest and survival. We also found that normal regulation of cyclin E restrains mitochondrial reactive oxygen species (ROS) accumulation and expression of genes that promote mitochondrial biogenesis and oxidative metabolism during terminal erythroid maturation. In the setting of dysregulated cyclin E expression, p53 is activated in BM erythroid cells as part of a DNA damage response-type pathway, which mitigates ineffective erythropoiesis, in contrast to the role of p53 induction in other models of dyserythropoiesis. Finally, cyclin E dysregulation and ROS accumulation induce histone H3 lysine 9 hyper-methylation and disrupt components of the normal terminal erythroid maturation gene expression program. Thus, ubiquitin-proteasome pathway control of G1-to-S-phase progression is intrinsically linked to regulation of metabolism and gene expression in terminally differentiating BM erythroid cells.