Ubiquitin-conjugating enzyme complex Uev1A-Ubc13 promotes breast cancer metastasis through nuclear factor-кB mediated matrix metalloproteinase-1 gene regulation

Wu, Zhaojia; Shen, Siqi; Zhang, Zhiling; Zhang, Weiwei; Xiao, Wei

doi:10.1186/bcr3692

Cited by 42 publications

(65 citation statements)

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“…Depletion of Ubc13 in these cells suppresses sister chromatid exchange and resensitizes these cells to cisplatin. Another recent study demonstrated that increased Uev1A levels can drive human breast cancer cell invasion and metastasis in mouse xenograft models in a manner that is dependent on Ubc13 43 . Ubc13 has also been shown to control breast cancer metastasis through the activation of a TAK1-p38 kinase 44 .…”

Section: Resultsmentioning

confidence: 99%

Covalent Inhibition of Ubc13 Affects Ubiquitin Signaling and Reveals Active Site Elements Important for Targeting

Hodge

Markin

et al. 2015

ACS Chem. Biol.

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Ubc13 is an E2 ubiquitin conjugating enzyme that functions in nuclear DNA damage signaling and cytoplasmic NF-κB signaling. Here we present the structures of complexes of Ubc13 with two inhibitors, NSC697923 and BAY 11-7082, which inhibit DNA damage and NF-κB signaling in human cells. NSC697923 and BAY 11-7082 both inhibit Ubc13 by covalent adduct formation through a Michael addition at the Ubc13 active site cysteine. The resulting adducts of both compounds exploit a binding groove unique to Ubc13. We developed a Ubc13 mutant which resists NSC697923 inhibition and, using this mutant, we show that the inhibition of cellular DNA damage and NF-κB signaling by NSC697923 is largely due to specific Ubc13 inhibition. We propose that unique structural features near the Ubc13 active site could provide a basis for the rational development and design of specific Ubc13 inhibitors.

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Section: Resultsmentioning

confidence: 99%

Covalent Inhibition of Ubc13 Affects Ubiquitin Signaling and Reveals Active Site Elements Important for Targeting

Hodge

Markin

et al. 2015

ACS Chem. Biol.

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“…These tumors exhibit increased expression of Matrix Metalloproteinase-1 (MMP1) through activation of NFκB signaling 8 (Fig. 2), in which MMPs are involved in extracellular matrix degradation for tumor cell migration and invasion 9 .…”

Section: The Overexpression Of E2s Supports Aberrant Oncogenic Signalmentioning

confidence: 99%

The importance of regulatory ubiquitination in cancer and metastasis

2017

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Ubiquitination serves as a degradation mechanism of proteins, but is involved in additional cellular processes such as activation of NFκB inflammatory response and DNA damage repair. We highlight the E2 ubiquitin conjugating enzymes, E3 ubiquitin ligases and Deubiquitinases that support the metastasis of a plethora of cancers. E3 ubiquitin ligases also modulate pluripotent cancer stem cells attributed to chemotherapy resistance. We further describe mutations in E3 ubiquitin ligases that support tumor proliferation and adaptation to hypoxia. Thus, this review describes how tumors exploit members of the vast ubiquitin signaling pathways to support aberrant oncogenic signaling for survival and metastasis.

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“…Medzi E2 ubikvitín ligázy so známou úlohou v kontrole procesov progresie bunečného cyklu patrí UBE2N/ UBE2V1 enzým, ktorý katalyzuje polyubikvitináciu na Lys63. Aberantná polyubikvitinácia na Lys63 spúšťa aberantnú signalizáciu NF-κB, ktorá u ma-márneho karcinómu môže viesť k hyperaktivácii zápalu v makroprostredí nádoru [16,17].…”

Section: Ubikvitinácia V Súvislosti S Karcinogenézouunclassified

Protein Ubiquitination Research in Oncology

Faktor¹,

Pjechová²,

Hernychová³

et al. 2019

Klin Onkol

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Regionální centrum aplikované molekulární onkologie, Masarykův onkologický ústav, Brno Súhrn Východiská: Ubikvitinácia je dôležitá posttranslačná modifikácia proteínov, ktorá reguluje mnoho signalizačných dráh u eukaryot. Aberantná ubikvitinácia je molekulárnou príčinou niektorých onkologických, neurodegeneratívnych, imunitných a kardiovaskulárnych ochorení. Rozvoj hmotnostne spektrometrických metód ponúka možnosť kvalitatívnej a kvantitatívnej analýzy ubikvitinácie proteínov v bio logickom materiáli onkologických pa cientov. Výskum ubikvitinácie môže objasniť molekulárnu príčinu zmeny hladiny niektorých proteínov, ktoré vystupujú ako onkogény alebo tumor supresory. Cieľ: Cieľom článku je priblížiť čitateľovi zmysel a dôležitosť ubikvitinácie v niektorých molekulárnych procesoch prebiehajúcich v ľudskom tele. Predovšetkým je dôraz kladený na popis zapojenia ubikvitinácie do malígnych procesov. Na literárnu rešerš nadväzujeme priblížením procesu hmotnostne spektrometrickej identifikácie ubikvitinácií prostredníctvom diglycylových zbytkov v sekvencii proteínu CHIP. Predstavujeme identifikáciu ubikvitinácie proteínov metódami tandemovej hmotnostnej spektrometrie, proces validácie tandemových hmotnostných spektier a popis časovej závislosti ubikvitinácie proteínu CHIP. Záver: Literárna rešerš oboznamuje čitateľa so známymi aberantnými mechanizmami ubikvitinácie u malígnych ochorení. Úspešne vytvorená hmotnostne spektrometrická metóda môže slúžiť na identifikáciu pozícií ubikvitinácie v sekvenciách proteínov obsiahnutých v lyzátoch nádorového tkaniva. Kľúčové slová ubikvitín-hmotnostná spektrometria-neoplazmy-proteín-proteomika Summary Background: Ubiquitination is a vital posttranslational protein modification involved in the regulation of many eukaryotic signalling pathways. Aberrant ubiquitin signalling is known to be a molecular causality of certain cancer, neurodegenerative, immune system or cardiovascular diseases. The recent development of mass spectrometry methods enables qualitative and quantitative ubiquitination analysis in biological material from cancer patients. Research of ubiquitination may clarify the molecular cause of aberrant changes in the protein level of tumour suppressors or oncogenes. Purpose: We aim to explain the meaning and importance of ubiquitination in certain molecular processes taking place in the human body. We hereby emphasise the connection between ubiquitination and malignant processes. A literature search is followed by introducing our mass spectrometry platform intended for ubiquitin identification via diglycyl remnants in the CHIP protein sequence. The aim is to introduce tandem mass spectrometry identification of ubiquitin modification, ubiquitination tandem mass spectra validation and the time-dependent manner of CHIP ubiquitination to the reader. Conclusion: A literature search familiarises the reader with known mechanisms of aberrant ubiquitination in malignant diseases. A successfully optimised mass spectrometry platform could serve as a potent tool for determining ubiquiti...

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Ubiquitin-conjugating enzyme complex Uev1A-Ubc13 promotes breast cancer metastasis through nuclear factor-кB mediated matrix metalloproteinase-1 gene regulation

Cited by 42 publications

References 46 publications

Covalent Inhibition of Ubc13 Affects Ubiquitin Signaling and Reveals Active Site Elements Important for Targeting

Covalent Inhibition of Ubc13 Affects Ubiquitin Signaling and Reveals Active Site Elements Important for Targeting

The importance of regulatory ubiquitination in cancer and metastasis

Protein Ubiquitination Research in Oncology

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