ORCID Profile
0000-0002-3859-0400
Current Organisations
Sanford-Burnham Medical Research Institute
,
University of Tennessee
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Publisher: Wiley
Date: 11-2002
DOI: 10.1093/EMBOJ/CDF576
Abstract: TRAF2 serves as a central regulator of the cellular response to stress and cytokines through the regulation of key stress-signaling cascades. Here we demonstrate that wild-type, but not RING mutant, Siah2 targets TRAF2 for ubiquitylation and degradation in vitro. Siah2 mediates equally efficient ubiquitylation of RING mutant TRAF2. In vivo, Siah2 primarily targets TRAF2 for degradation under stress conditions. Tumor necrosis factor-alpha (TNF-alpha) and actinomycin D treatment results in accelerated TRAF2 degradation in wild-type mouse embryo fibroblasts (MEFs), as compared with Siah2(-/-) cells. Similarly, TRAF2 half-life is prolonged in Siah2(-/-) compared with wild-type MEFs subjected to stress stimuli. Siah2 efficiently decreases TNF-alpha-dependent induction of JNK activity and transcriptional activation of NF-kappaB. Apoptosis induced by TNF-alpha and actinomycin D treatment is increased upon expression of Siah2, or attenuated upon expression of TRAF2 or RING mutant Siah2. Identifying Siah2 as a regulator of TRAF2 stability reveals its role in the regulation of TRAF2 signaling following exposure to stress.
Publisher: Public Library of Science (PLoS)
Date: 21-10-2011
Publisher: Public Library of Science (PLoS)
Date: 23-12-2010
Publisher: Elsevier BV
Date: 12-2012
Publisher: American Association for Cancer Research (AACR)
Date: 04-2012
DOI: 10.1158/0008-5472.CAN-11-3310
Abstract: Tumor hypoxia is associated with resistance to antiangiogenic therapy and poor prognosis. The Siah E3 ubiquitin ligases regulate the hypoxic response pathway by modulating the turnover of the master proangiogenic transcription factor hypoxia-inducible factor-1α (Hif-1α). In this study, we show that genetic deficiency in the Siah family member Siah2 results in vascular normalization and delayed tumor growth in an established transgenic model of aggressive breast cancer. Tumors arising in a Siah2−/− genetic background showed increased perfusion and pericyte-associated vasculature, similar to that occurring with antiangiogenic therapy. In support of the role of Siah2 in regulating levels of Hif-1α, expression of angiogenic factors was decreased in Siah2−/− tumors. Blood vessel normalization in Siah2−/− tumors resulted in an increased response to chemotherapy and prolonged survival. Together, our findings offer a preclinical proof of concept that targeting Siah2 is sufficient to attenuate Hif-1α–mediated angiogenesis and hypoxia signaling, thereby improving responses to chemotherapy. Cancer Res 72(7) 1694–704. ©2012 AACR.
Publisher: Wiley
Date: 30-05-2015
DOI: 10.1111/PCMR.12382
Location: Israel
Location: United States of America
Location: United States of America
Location: United States of America
Location: United States of America
No related grants have been discovered for ZEEV RONAI.