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T Traboulsi, M El Ezzy, J L Gleason, and S Mader

pure AEs and SERMs act via different molecular mechanisms. Indeed, although 4-hydroxytamoxifen increases overall ERα protein levels, pure AEs accelerate ERα turnover through the ubiquitin–proteasome pathway in ERα-positive breast cancer cells and in

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Z G Song, X H Zhang, L X Zhu, H C Jiao, and H Lin

skeletal muscle ( Rudnicki et al . 1993 ). In chickens, MYOD and MYF5 are associated with post-hatch chicken myogenesis ( Day et al . 2009 ). Enhanced proteolysis in atrophying muscles derives mainly from general activation of the ubiquitin

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Tingyuan Ren, Yuping Zhu, Xuejuan Xia, Yongbo Ding, Jing Guo, and Jianquan Kan

(Fogg et al . 2011). The ubiquitin–proteasome pathway (UPP) connects the ubiquitin to the target protein by a three-enzyme cascade. UPP is the most vital and selective protein degradation pathway in mammalian cells, and it mediates the degradation of 80

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T Yamaguchi, A Kurisaki, N Yamakawa, K Minakuchi, and H Sugino

). Smad7 also recruits Smad ubiquitin regulatory factor 1 (Smurf1) to the type I receptors to promote ubiquitination of the receptors ( Kavsak et al. 2000 , Ebisawa et al. 2001 ). FKBP12 is a cytoplasmic protein that binds to the

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Nina Gustafsson Sheppard, Nina Heldring, and Karin Dahlman-Wright

stimulation has been reported ( Ellison-Zelski et al . 2009 ). However, in breast cancer, this inverse relationship between ERα and its agonist is lost, indicating deregulation of ERα expression ( Khan et al . 1999 ). RBCK1 is an E3 ubiquitin ligase

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Jiayu Zhang, Chengwei Chen, Liang Wu, Qiang Wang, Jiawei Chen, Sifang Zhang, and Zhenguo Chen

). However, whether BRCC3 regulates NLRP3 ubiquitination in HG-induced Müller cells remains unclear. Since the ubiquitin–proteasome system (UPS) is the main intracellular pathway mediating protein degradation ( Campello et al. 2013 ), we supposed that the

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Tiziana de Cristofaro, Anna Mascia, Andrea Pappalardo, Barbara D'Andrea, Lucio Nitsch, and Mariastella Zannini

(inhibiting or activating) gene expression by altering transcription factor stability, protein–protein interaction and subcellular localization of target proteins ( Hay 2005 , Heun 2007 ). Enzymes involved in small ubiquitin-like modifier (SUMO) conjugation

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Xu-guang Zhu, Dong Wook Kim, Michael L Goodson, Martin L Privalsky, and Sheue-Yann Cheng

adipogenesis was accompanied by progressive loss of NCoR1 protein. The downregulation of NCoR1 depended on the TRs and the ubiquitin ligase mSiah2. A more severe impairment of T 3 -stimulated adipogenesis in L1-α1PV cells than in L1-β1PV cells was associated

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Q Wu, XF Lin, XF Ye, B Zhang, Z Xie, and WJ Su

Retinoic acid receptor alpha (RARalpha) plays an important role in mediating all-trans retinoic acid (ATRA) signals. In this study, we found that ATRA up-regulated RARalpha mRNA and protein expression in gastric cancer BGC-823 cells. However, in breast cancer MCF-7 cells it down-regulated RARalpha protein expression with no effect on its RARalpha mRNA. Immunoprecipitation/Western blot analysis showed that, although sumoylated and ubiquitinated RARalpha existed simultaneously in both cancer cell lines, ATRA exerted different regulatory effects on sumoylation and ubiquitination of RARalpha. In MCF-7 cells, ATRA treatment enhanced the ubiquitination of RARalpha and the subsequent degradation of RARalpha through the ubiquitin/proteasome pathway. This resulted in a reduction in the DNA binding activity of RARalpha/retinoid X receptor alpha (RXRalpha) heterodimer, the separation of RXRalpha from RARalpha and the translocation of RXRalpha from the nucleus to the cytoplasm. By contrast, in BGC-823 cells, ATRA augmented sumoylation, not ubiquitination, of RARalpha. The stability of sumoylated RARalpha was significantly stronger than in non-sumoylated RARalpha. These results also showed an increase in the DNA binding activity of the RARalpha/RXRalpha heterodimer and the stability of nuclear localization of this heterodimer, which normally facilitates the ATRA signal transduction. In conclusion, our results reveal a novel mechanism for the regulation of RARalpha-dependent signal transduction through the ubiquitin/proteasome pathway in breast cancer cells and the sumoylation pathway in gastric cancer cells.

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S Kobayashi, H Shibata, I Kurihara, K Yokota, N Suda, I Saito, and T Saruta

Chicken ovalbumin upstream promoter-transcription factors (COUP-TFs) are orphan receptors involved in regulation of neurogenesis and organogenesis. COUP-TF family members are generally considered to be transcriptional repressors and several mechanisms have been proposed to underlie this activity. To explore novel transcriptional coregulators for COUP-TFs, we used the COUP-TFI as bait in a yeast two-hybrid screen of an adrenocortical adenoma cDNA library. We have identified Ubc9, a class E2 conjugating enzyme of small ubiquitin-related modifier (SUMO)-1 as a COUP-TFI corepressor. Ubc9 interacts with COUP-TFI in yeast and in glutathione S-transferase pulldown and coimmunoprecipitation assays. Fluorescence imaging studies show that both Ubc9 and COUP-TFI are colocalized in the nuclei of transfected COS-1 cells. The C-terminal region of Ubc9 encoding amino acids 59-158 interacts with the C-terminus of COUP-TFI encoding amino acids 383-403, in which transcriptional repression domains are located. Mammalian one-hybrid assays utilizing a variety of Ubc9 fragments fused to Gal4 DNA-binding domain show that a Ubc9 fragment encoding amino acids 1-89 contains autonomous transferrable repression domain. Transfection of Ubc9 into COS-1 cells markedly enhances transcriptional repression by Gal4 DNA-binding domain-fused to COUP-TFI(155-423), but not by Gal4-COUP-TFI(155-388) which lacks a repressor domain. Coexpression of a C-terminal deletion mutant of Ubc9(1-58), which fails to interact with COUP-TFI, but retains a transcriptional repression domain, has no effect on Gal4-COUP-TFI-mediated repression activity. These findings indicate that interaction of Ubc9 with COUP-TFI is crucial for the corepressor function of Ubc9. Overexpression of Ubc9 similarly enhances COUP-TFI-dependent repression of the promoter activity of the bovine CYP17 gene encoding steroid 17alpha-hydroxylase. In addition, the C93S mutant of Ubc9, which abrogates SUMO-1 conjugation activity, continues to function as a COUP-TFI corepressor. Our studies indicate that Ubc9 functions as a novel COUP-TFI corepressor, the function of which is distinct from its SUMO-1 conjugating enzyme activity.