Abstract
The ubiquitin–proteasome system (UPS) participates in both physiological and pathological processes through the posttranslational regulation of intracellular signal transduction pathways. F-box and WD-40 domain protein 11 (Fbxw11) is a component of the SCF (Skp1–Cul1–F-box) E3 ubiquitin ligase complex. Fbxw11 regulates various signal transduction pathways, and it may have pathological roles in tumorigenesis. However, the role of Fbxw11 in the development of leukemia and the underlying mechanisms remain largely unknown. In this study, Fbxw11 expression was aberrantly upregulated in patients with lymphocytic leukemia. Its expression was dramatically decreased in patients who achieved complete remission (CR) after chemotherapy. The high level of Fbxw11 expression in L1210 lymphocytic leukemia cells stimulated cell proliferation in vitro and tumor formation in vivo. The effects were mediated by the stimulation of cell cycle progression rather than the induction of apoptosis. Furthermore, a bioinformatics analysis suggested concomitant activation of the NF-κB and β-catenin/TCF signaling pathways, which were confirmed by reporter gene assays. Moreover, blocking experiments suggested the involvement of both pathways in the growth-promoting effects of Fbxw11. Our results reveal the role of Fbxw11 in lymphocytic leukemia cells and imply that Fbxw11 may serve as a potential molecular target for the treatment of lymphocytic leukemia.
Highlights
Hematopoiesis is strictly regulated by complicated intercellular communication from the hematopoietic microenvironment through sophisticated signal transduction networks
In patients with ALL presenting with cytogenetic abnormalities, Fbxw[11] was expressed at high levels observed in most subtypes, except for B-cell acute lymphocytic leukemia (B-ALL) with t(8;14) or T-cell acute lymphocytic leukemia (T-ALL) (Fig. 1b)
The ubiquitin–proteasome system (UPS) is an important protein control system that participates in many physiological processes, such as cell proliferation, differentiation, and signal transduction
Summary
Hematopoiesis is strictly regulated by complicated intercellular communication from the hematopoietic microenvironment through sophisticated signal transduction networks. Dysregulation of signal transduction will disrupt the balance of normal hematopoiesis and cause various blood diseases. Leukemia is regarded as a clonal disease[1,2], and many intrinsic and extrinsic factors have been verified to play parts in the initiation and development of leukemia[3,4]. The ubiquitin–proteasome system (UPS), which is the main pathway for the degradation of short-period proteins in cells, is involved in the posttranslational regulation of numerous intracellular signal transduction pathways[11]. F-box family proteins, which are further divided into Fbxw, Fbxl, and Fbxo subfamilies based on protein structure, determine the specificity of substrate degradation by identifying and Official journal of the Cell Death Differentiation Association
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