Retinoic acid receptor alpha (RARα) has a critical role in the differentiation process of osteosarcoma cells induced by all-trans retinoic acid (ATRA). However, degradation of RARα through ubiquitin proteasome pathway weakens the differentiation efficiency of osteosarcoma cells. In this study, we discover that murine double minute-2 (MDM2) acts as an E3 ubiquitin ligase to target RARα for degradation. We observe that MDM2 is required for RARα polyubiquitination and proteasomal degradation because downregulation of MDM2 by short hairpin RNA results in the accumulation of RARα, and MDM2 overexpression promotes the degradation of RARα. We also demonstrate that the N-terminal domain of MDM2 (amino acids 1-109) is the major RARα-binding site. Importantly, endogenous MDM2 levels are not only upregulated in human primary osteosarcoma blasts but are also inversely correlated with the level of osteopontin, which is a marker of bone differentiation. Moreover, MDM2 impairs the ATRA-induced osteoblastic differentiation of osteosarcoma cells, whereas an inhibitor of the MDM2 ubiquitin ligase synergizes with ATRA to enhance the differentiation of osteosarcoma cells and primary osteosarcoma blasts. Therefore, our study indicates that MDM2 serves as an E3 ubiquitin ligase to regulate the degradation of RARα and suggests that MDM2 is a novel therapeutic target for ATRA-based differentiation therapeutic approaches in osteosarcoma.
Adalimumab, a fully human monoclonal antibody against tumor necrosis factor, demonstrates good efficacy in the treatment of moderate-to-severe chronic plaque psoriasis, especially in the patients with psoriatic arthritis. 1 However, in some cases, the skin lesions could not be completely cleared by using adalimumab alone. The topical therapy should now be combined with biologic to improve the skin lesions. Topical corticosteroids and calcineurin inhibitors are the common choices, but in view of their limitations of efficacy and tolerability, new treatments options are needed in clinic practice.As a potential therapeutic target for inflammatory skin diseases, phosphodiesterase 4 (PDE-4) inhibitor decrease the release of cytokines through increasing intracellular cAMP levels. 2,3 As a novel nonsteroidal PDE-4 inhibitor, Crisaborole not only inhibits type 2 cytokines such as interleukin 4 (IL-4), IL-13 and so on, but also reduces cytokines including tumor necro-
In the past decade, the emergence of biologics targeting human cytokine networks has advanced a new era in atopic dermatitis therapy. Dupilumab, in particular, the most widely studied and used IL-4/IL-13 inhibitor, has been considered a milestone in the treatment of patients with moderate-to-severe atopic dermatitis. In addition to the IL-4 and IL-13 pathways, many other cytokines and receptors have been newly targeted as therapeutic options. In this review, the authors provide an overview of the approved and tested biologics and JAK inhibitors for the treatment of atopic dermatitis, including their advantages and limitations.
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