Cardiovascular disease is a major cause of death worldwide. Mitogen-activated protein kinase (MAPK) signal cascades signaling pathways play crucial roles in cardiovascular pathophysiology. Apoptosis signal-regulating kinase (ASK) family members ASK1, ASK2 and ASK3 are the key molecules in MAPK signal cascades and are activated by various stresses. ASK1 is the most extensively studied MAPKKK and is involved in regulation of the cellular functions such as cell survival, proliferation, inflammation and apoptosis. The current review focuses on the relationship between ASK1 and cardiovascular disease, while exploring the novel therapeutic strategies for cardiovascular disease involved in the ASK1 signal pathway.
Novel targeted agents used in therapy of lymphoid malignancies are recognized to have complex immune-mediated effects. Sumoylation, a posttranslational modification of target proteins by small ubiquitin-like modifiers (SUMO), regulates a variety of cellular processes indispensable in immune cell activation. Despite this, the role of sumoylation in T cell biology in context of cancer is not known. TAK-981 (subasumstat) is a small molecule inhibitor of the SUMO-activating enzyme (SAE) that forms a covalent adduct with an activated SUMO protein. Using T cells derived from patients with chronic lymphocytic leukemia (CLL), we demonstrate that targeting SAE activates type I interferon response. This is accompanied by largely intact T-cell activation in response to T-cell receptor engagement, with increased expression of CD69 and CD38. Furthermore, TAK-981 decreases Treg differentiation and enhances secretion of interferon-γ by CD4+ and CD8+ T-cells. These findings were recapitulated in mouse models, suggesting an evolutionarily conserved mechanism of T cell activation regulated by SUMO modification. Relevant to the consideration of TAK-981 as an effective agent for immunotherapy in hematological malignancies, we demonstrate that the downstream impact of TAK-981 administration is enhancement of the cytotoxic function of CD8+ T cells, thus uncovering immune implications of targeting sumoylation in lymphoid neoplasia.
<div>Abstract<p>Novel targeted agents used in therapy of lymphoid malignancies are recognized to have complex immune-mediated effects. Sumoylation, a posttranslational modification of target proteins by small ubiquitin-like modifiers (SUMO), regulates a variety of cellular processes indispensable in immune cell activation. Despite this, the role of sumoylation in T-cell biology in context of cancer is not known. TAK-981 (subasumstat) is a small-molecule inhibitor of the SUMO-activating enzyme (SAE) that forms a covalent adduct with an activated SUMO protein. Using T cells derived from patients with chronic lymphocytic leukemia (CLL), we demonstrate that targeting SAE activates type I IFN response. This is accompanied by largely intact T-cell activation in response to T-cell receptor engagement, with increased expression of CD69 and CD38. Furthermore, TAK-981 decreases regulatory T cell (Treg) differentiation and enhances secretion of IFNγ by CD4<sup>+</sup> and CD8<sup>+</sup> T cells. These findings were recapitulated in mouse models, suggesting an evolutionarily conserved mechanism of T-cell activation regulated by SUMO modification. Relevant to the consideration of TAK-981 as an effective agent for immunotherapy in hematologic malignancies, we demonstrate that the downstream impact of TAK-981 administration is enhancement of the cytotoxic function of CD8<sup>+</sup> T cells, thus uncovering immune implications of targeting sumoylation in lymphoid neoplasia.</p></div>
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