title: Fbw7-dependent cyclin E regulation ensures terminal maturation of bone marrow erythroid cells by restraining oxidative metabolism.
abstract: 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.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.affiliation: 1] Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA [2] Driskill Graduate Program in Life Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Swartz
authors.affiliation: 1] Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA [2] Driskill Graduate Program in Life Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: K T
authors.initials: KT
authors.lastname: Siu
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: M
authors.initials: M
authors.lastname: Bhattacharyya
authors.affiliation: 1] Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA [2] Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Minella
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D019927:Cyclin E / Q000378:metabolism*; D041905:Erythroid Cells / Q000378:metabolism*; D044783:F-Box Proteins / Q000502:physiology*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
chemical_list: D014408:Biomarkers, Tumor; D019927:Cyclin E; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513272:Fbxw7 protein, mouse; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases