{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T01:48:41Z","timestamp":1792288121182,"version":"4.4.0"},"reference-count":55,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,10,4]],"date-time":"2024-10-04T00:00:00Z","timestamp":1728000000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100020581","name":"Fondazione AIRC per la ricerca sul cancro ETS","doi-asserted-by":"publisher","award":["IG 2022 \u2013 27366"],"award-info":[{"award-number":["IG 2022 \u2013 27366"]}],"id":[{"id":"10.13039\/100020581","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020581","name":"Fondazione AIRC per la ricerca sul cancro ETS","doi-asserted-by":"publisher","award":["IG 2019 \u2013 23232"],"award-info":[{"award-number":["IG 2019 \u2013 23232"]}],"id":[{"id":"10.13039\/100020581","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:p>\n                    The HECT\u2010type E3 ubiquitin WWP1 (also known as NEDD4\u2010like E3 ubiquitin\u2010protein ligase WWP1) acts as an oncogenic factor in acute myeloid leukemia (AML) cells.\n                    <jats:italic>WWP1<\/jats:italic>\n                    overexpression in AML confers a proliferative advantage to leukemic blasts (abnormal immature white blood\u00a0cells) and counteracts apoptotic cell death and differentiation. In an\u00a0effort to elucidate the molecular basis of WWP1 oncogenic activities, we identified WWP1 as a previously unknown negative regulator of thioredoxin\u2010interacting protein (TXNIP)\u2010mediated reactive oxygen species (ROS) production in AML cells. TXNIP inhibits the disulfide reductase enzymatic activity of thioredoxin (Trx), impairing its antioxidant function and, ultimately, leading to the disruption of cellular redox homeostasis. In addition, TXNIP restricts cell growth and survival by blocking glucose uptake and metabolism. Here, we found that WWP1 directly interacts with TXNIP, thus promoting its ubiquitin\u2010dependent proteasomal proteolysis. As a result, accumulation of TXNIP in response to WWP1 inactivation in\u00a0AML blasts reduces Trx activity and increases ROS production, hence\u00a0inducing cellular oxidative stress. Increased ROS generation in WWP1\u2010depleted cells culminates in DNA strand breaks and subsequent apoptosis. Coherently with TXNIP stabilization following WWP1 inactivation, we also observed an impairment of both glucose up\u2010take and consumption. Hence, a contribution to the increased cell death observed in WWP1\u2010depleted cells also possibly arises from the attenuation of glucose up\u2010take and glycolytic flux resulting from TXNIP accumulation. Future studies are needed to establish whether TXNIP\u2010dependent deregulation of redox homeostasis in WWP1\u2010overexpressing blasts may affect the response of leukemic cells to chemotherapeutic drugs.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.13722","type":"journal-article","created":{"date-parts":[[2024,10,4]],"date-time":"2024-10-04T06:39:50Z","timestamp":1728023990000},"page":"133-150","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Thioredoxin\u2010interacting protein (\n                    <scp>TXNIP<\/scp>\n                    ) is a substrate of the\n                    <scp>NEDD4<\/scp>\n                    \u2010like\n                    <scp>E3<\/scp>\n                    ubiquitin\u2010protein ligase\n                    <scp>WWP1<\/scp>\n                    in cellular redox state regulation of acute myeloid leukemia 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