High expression of UCH37 is significantly associated with poor prognosis in human epithelial ovarian cancer

Wang, Lin; Chen, Yanjie; Xu, Kai; Wang, Yayun; Shen, Xizhong; Tu, Ruiqin

doi:10.1007/s13277-014-2446-3

Cited by 42 publications

(34 citation statements)

References 16 publications

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“…Uch37 is upregulated in multiple cancers, including epithelial ovarian cancer, hepatocellular carcinoma and oesophageal squamous cell carcinoma with high Uch37 expression associated with poor prognosis616263. A compound with a similar reactive group compared with RA190 was previously reported to react with the proteasome deubiquitinating enzymes53, in support of our finding that RA190 directly targets and inhibits Uch37.…”

Section: Discussionsupporting

confidence: 86%

Structure of the Rpn13-Rpn2 complex provides insights for Rpn13 and Uch37 as anticancer targets

et al. 2017

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Proteasome–ubiquitin receptor hRpn13/Adrm1 binds and activates deubiquitinating enzyme Uch37/UCHL5 and is targeted by bis-benzylidine piperidone RA190, which restricts cancer growth in mice xenografts. Here, we solve the structure of hRpn13 with a segment of hRpn2 that serves as its proteasome docking site; a proline-rich C-terminal hRpn2 extension stretches across a narrow canyon of the ubiquitin-binding hRpn13 Pru domain blocking an RA190-binding surface. Biophysical analyses in combination with cell-based assays indicate that hRpn13 binds preferentially to hRpn2 and proteasomes over RA190. hRpn13 also exists outside of proteasomes where it may be RA190 sensitive. RA190 does not affect hRpn13 interaction with Uch37, but rather directly binds and inactivates Uch37. hRpn13 deletion from HCT116 cells abrogates RA190-induced accumulation of substrates at proteasomes. We propose that RA190 targets hRpn13 and Uch37 through parallel mechanisms and at proteasomes, RA190-inactivated Uch37 cannot disassemble hRpn13-bound ubiquitin chains.

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Section: Discussionsupporting

confidence: 86%

Structure of the Rpn13-Rpn2 complex provides insights for Rpn13 and Uch37 as anticancer targets

et al. 2017

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“…Recruitment of UCH37 to these complexes depends on its autoinhibitory C-terminal domain (UCH37 CTD ) (Yao et al, 2008; Yao et al, 2006), which follows the N-terminal catalytic UCH domain (UCH37 UCH ) that contains the active site residues and binds ubiquitin (Burgie et al, 2011; Maiti et al, 2011; Morrow et al, 2013; Nishio et al, 2009) in the same manner as other UCH enzymes (Boudreaux et al, 2010; Johnston et al, 1997; Johnston et al, 1999). It is not known which of these complexes, which appear to have no other subunits in common, mediates the essential UCH37 function that results in: (1) embryonic lethality due to severe defects in brain development upon genomic deletion of UCH37 in mice (Al-Shami et al, 2010) and (2) its implication in multiple cancers (Chen et al, 2012; Fang et al, 2012; Wang et al, 2014). Regardless, the potential of UCH37 as a therapeutic target has been noted (Chen et al, 2013; Cutts et al, 2011; D'Arcy et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Structural Basis for the Activation and Inhibition of the UCH37 Deubiquitylase

et al. 2015

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SUMMARY The UCH37 deubiquitylase functions in two large and very different complexes, the 26S proteasome and the INO80 chromatin remodeler. We have performed biochemical characterization and determined crystal structures of UCH37 in complexes with RPN13 and NFRKB, which mediate its recruitment to proteasome and INO80, respectively. RPN13 and NFRKB make similar contacts to the UCH37 C-terminal domain, but quite different contacts to the catalytic UCH domain. RPN13 can activate UCH37 by disrupting dimerization, although physiologically-relevant activation likely results from stabilization of a surface competent for ubiquitin binding and modulation of the active-site crossover loop. In contrast, NFRKB inhibits UCH37 by blocking the ubiquitin-binding site and by disrupting the enzyme active site. These findings reveal remarkable commonality in mechanisms of recruitment, yet very different mechanisms of regulating enzyme activity, and provide a foundation for understanding the role of UCH37 in the unrelated proteasome and INO80 complexes.

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“…UCHL5 is up-regulated in most tumor tissues of ovarian cancer patients and is significantly associated with poor prognosis in human epithelial ovarian cancer37. Recently, UCHL5 as a new cancer therapeutic potential target has been noted222324.…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin carboxyl-terminal hydrolase-L5 promotes TGFβ-1 signaling by de-ubiquitinating and stabilizing Smad2/Smad3 in pulmonary fibrosis

Jacko

Tan

et al. 2016

Sci Rep

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Transforming growth factor β-1 (TGFβ-1)-induced phosphorylation of transcription factors Smad2 and Smad3 plays a crucial role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, the molecular regulation of Smad2/Smad3 proteins stability remains a mystery. Here, we show that ubiquitin carboxyl-terminal hydrolase-L5 (UCHL5 or UCH37) de-ubiquitinates both Smad2 and Smad3, up-regulates their stability, and promotes TGFβ-1-induced expression of profibrotic proteins, such as fibronectin (FN) and α-smooth muscle actin (α-SMA). Inhibition or down-regulation of UCHL5 reduced Smad2/Smad3 levels and TGFβ-1-induced the expression of FN and α-SMA in human lung fibroblast. We demonstrate that Smad2 and Smad3 ubiquitination was diminished by over-expression of UCHL5, while it was enhanced by inhibition or down-regulation of UCHL5. UCHL5 is highly expressed in IPF lungs. UCHL5, Smad2, and Smad3 levels were increased in bleomycin-injured lungs. Administration of UCHL5 inhibitor, b-AP15, reduced the expression of FN, type I collagen, Smad2/Smad3, and the deposition of collagen in lung tissues in a bleomycin-induced model of pulmonary fibrosis. Our studies provide a molecular mechanism by which UCHL5 mitigates TGFβ-1 signaling by stabilizing Smad2/Smad3. These data indicate that UCHL5 may contribute to the pathogenesis of IPF and may be a potential therapeutic target.

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High expression of UCH37 is significantly associated with poor prognosis in human epithelial ovarian cancer

Cited by 42 publications

References 16 publications

Structure of the Rpn13-Rpn2 complex provides insights for Rpn13 and Uch37 as anticancer targets

Structure of the Rpn13-Rpn2 complex provides insights for Rpn13 and Uch37 as anticancer targets

Structural Basis for the Activation and Inhibition of the UCH37 Deubiquitylase

Ubiquitin carboxyl-terminal hydrolase-L5 promotes TGFβ-1 signaling by de-ubiquitinating and stabilizing Smad2/Smad3 in pulmonary fibrosis

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