Abstract
Abstract Mitochondria are highly motile organelles that constantly undergo fission and fusion. Impairment of mitochondrial dynamics is associated with mitochondrial dysfunction and is frequently linked to the pathogenesis of neurodegenerative diseases and cancer. We have previously shown that biallelic inactivation of the suppressor of cytokine signaling 6 (SOCS6) is a frequent event in human gastric cancer, and that overexpression of SOCS6 inhibits cell growth as well as colony formation in soft agar, suggesting a potential role of SOCS6 as a tumor suppressor. We also showed that SOCS6 is targeted to mitochondria, and induces mitochondrial fragmentation accompanied with intrinsic apoptosis. SOCS6 induces mitochondrial fragmentation is in part mediated through its interaction with DRP1 and regulation of DRP1 fission activity. In this study, we further showed that SOCS6 interacts with the Elongin B/C and Cullin 5 forming an ECS E3 ubiquitin ligase complex, and that formation of an intact ECS E3 ligase complex is important for SOCS6-mediated mitochondrial fragmentation. First, the interaction of SOCS6 with Elongin B/C and/or Cullin 5 prolonged SOCS6 stability. Second, mutations of the conserved Leu500 and Cys504 residues in SOCS6 BC-box which are critical for Elongin B/C binding yielded a SOCS6 mutant failed to induce mitochondrial fragmentation and apoptosis. Most importantly, ablation of Elongin C activity protected cells from SOCS6-mediated mitochondrial fission. Taken together, our data suggest an important role of SOCS6 in modulating mitochondrial dynamics that is dependent on ECS E3 ubiquitin ligase complex activity. Citation Format: Huan-Yu Lin, Shiu-Ting Lin, Mei-June Wang, Jeou-Yuan Chen. Suppressor of cytokine signaling 6 (SOCS6) promotes mitochondrial fission through E3 ubiquitin ligase complex activity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1699. doi:10.1158/1538-7445.AM2013-1699
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