Abstract
Anaphase promoting complex/cyclosome (APC/C) is essential for cell cycle progression. Recently, its non-mitotic functions were also reported but less studied in several tissues including hematopoietic cells. Here, we developed an inducible Anapc2 (a core subunit of APC/C) knockout mice. The animals displayed a fatal bone marrow failure within 7 days after knockout induction. Their hematopoietic stem and progenitor cells (HSPCs) demonstrated a sharp decline and could form little colony. Further, the results of BrdU label-retaining cell assay showed that the dormant HPSCs lost rapidly. Analysis of cell cycle regulators, Skp2, P27, Cdk2, and Cyclin E1, suggested that these quiescent stem cells underwent a shift from quiescence to mitosis followed by apoptosis. We next detected Anapc2-expression in the CD34+ HSPCs of patients with aplastic anemia. CD34+ cells were markedly decreased in the bone marrow and Anapc2-expression in the residual CD34+ cells was undetectable, suggesting that APC/C was deficient and might have a relationship with the pathogenesis of aplastic anemia.
Highlights
Hematopoietic stem cells (HSPCs) are tightly regulated by the extrinsic and intrinsic factors [1,2,3,4,5]
The Anapc2flox/flox mice were used as control (Ctrl). (E) Quantitative Polymerase chain reaction (PCR) to determine relative Anapc2 mRNA expression level using bone marrow (BM) cells
We investigate the role of Anaphase promoting complex/cyclosome (APC/C) in the hematopoietic system through an APC/C-deficient mouse model in which Anapc2, the gene encoding the essential APC/C subunit Anapc2, is conditionally deleted
Summary
Hematopoietic stem cells (HSPCs) are tightly regulated by the extrinsic and intrinsic factors [1,2,3,4,5]. Among them various cell-cycle factors such as cyclins and cyclin-dependent kinase inhibitors (CKIs) are important and regulated by Anaphase-promoting complex/cyclosome (APC/C). APC/C is one of important E3 ubiquitin ligase complexes that assemble polyubiquitin chains on specific substrates. It plays distinct roles in the M and G1 phase transiently with two co-activators Cdc and Cdh1 [6–. APC/CCdh degrades Cdc and other cyclins such as Aurora and Plk to advance the cell cycle into the G1 phase [6,7,8]. In the G1 phase, type A and B cyclins and DNA replication regulators such as Skp, Geminin, Cdc 6, Tk1 and Tmpk are degraded by APC/ CCdh, guaranteeing a sufficient preparation for entering into the S phase [6,7,8]
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