The Ubiquitin-Conjugating Enzyme E2-EPF Is Overexpressed in Primary Breast Cancer and Modulates Sensitivity to Topoisomerase II Inhibition

Tedesco, Donato; Zhang, Jianhuan; Trinht, Lan; Lalehzadeh, Guita; Meisner, René; Yamaguchi, Ken; Ruderman, Daniel; Dinter, Harald; Zajchowski, Deborah A.

doi:10.1593/neo.07385

Cited by 47 publications

(29 citation statements)

References 18 publications

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“…Recent studies have shown that UBE2S is also overexpressed in cancers. High expression of UBE2S was observed in cervical, breast, and kidney cancers [30][31][32][33], but the physiological role of UBE2S in cancer still remains uncertain. In this report, we show that UBE2S depletion suppressed migration, spreading, and invasion of breast cancer cells.…”

Section: Introductionmentioning

confidence: 99%

UBE2S is associated with malignant characteristics of breast cancer cells

Ayesha¹,

Hyodo²,

Asano³

et al. 2015

Tumor Biol.

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Ubiquitination is essential for various biological processes, such as signal transduction, intracellular trafficking, and protein degradation. Accumulating evidence has demonstrated that ubiquitination plays a crucial role in cancer development. In this report, we examine the expression and function of ubiquitin-conjugating enzyme E2S (UBE2S) in breast cancer. Immunohistochemical analysis revealed that UBE2S is highly expressed in breast cancer. The depletion of UBE2S by siRNA induced disruption of the actin cytoskeleton and focal adhesions. Interestingly, phosphorylation of FAK at Tyr397, which is important for the transduction of integrin-mediated signaling, was significantly reduced by UBE2S knockdown. We also show that UBE2S knockdown suppressed the malignant characteristics of breast cancer cells, such as migration, invasion, and anchorage-independent growth. Our results indicate that UBE2S could be a potential target for breast cancer treatment.

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Section: Introductionmentioning

confidence: 99%

UBE2S is associated with malignant characteristics of breast cancer cells

Ayesha¹,

Hyodo²,

Asano³

et al. 2015

Tumor Biol.

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“…Overexpression of Ube2S transforms cells in culture and promotes tumor growth in mice (19,20). This suggests that Ube2S levels have to be regulated, and indeed, Ube2S is degraded during G1 (Fig.…”

Section: Ube2s Is Regulated By Apc/c-dependent Degradationmentioning

confidence: 96%

Identification of a physiological E2 module for the human anaphase-promoting complex

Williamson

Wickliffe

Mellone

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

270

380

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Ubiquitination by the anaphase-promoting complex (APC/C) is essential for proliferation in all eukaryotes. The human APC/C promotes the degradation of mitotic regulators by assembling K11-linked ubiquitin chains, the formation of which is initiated by its E2 UbcH10. Here, we identify the conserved Ube2S as a K11-specific chain elongating E2 for human and Drosophila APC/C. Ube2S depends on the cell cycledependent association with the APC/C activators Cdc20 and Cdh1 for its activity. While depletion of Ube2S already inhibits APC/C in cells, the loss of the complete UbcH10/Ube2S-module leads to dramatic stabilization of APC/C substrates, severe spindle defects, and a strong mitotic delay. Ube2S and UbcH10 are tightly co-regulated in the cell cycle by APC/C-dependent degradation. We conclude that UbcH10 and Ube2S constitute a physiological E2-module for APC/C, the activity of which is required for spindle assembly and cell division.K11-linked chain ͉ proteasome ͉ ubiquitin

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“…Recently, UBE2S was found to be overexpressed in breast tumors and its expression correlates with genes that function in the G2/M phases of the cell cycle, including CYCLIN B2, CDC20, and UBE2C (UbcH10). Moreover, UBE2S protein oscillates through the cell cycle and reaches peak level at late mitosis (22).…”

Section: Securin With a Single Lysine Can Support Efficient Apc-depenmentioning

confidence: 99%

UBE2S drives elongation of K11-linked ubiquitin chains by the Anaphase-Promoting Complex

Merbl

Huo

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

205

251

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The Anaphase-Promoting Complex (APC) is an E3 ubiquitin ligase that regulates mitosis and G1 by sequentially targeting cell-cycle regulators for ubiquitination and proteasomal degradation. The mechanism of ubiquitin chain formation by APC and the resultant chain topology remains controversial. By using a single-lysine APC substrate to dissect the topology of ubiquitinated substrates, we find that APC-catalyzed ubiquitination has an intrinsic preference for the K11 linkage of ubiquitin that is essential for substrate degradation. K11 specificity is determined by an E2 enzyme, UBE2S/E2-EPF, that elongates ubiquitin chains after the substrates are pre-ubiquitinated by UbcH10 or UbcH5. UBE2S copurifies with APC; dominant-negative Ube2S slows down APC substrate degradation in functional cell-cycle extracts. We propose that Ube2S is a critical, unique component of the APC ubiquitination pathway.uring protein ubiquitination, a lysine residue on a target protein is conjugated to ubiquitin through an enzymatic cascade involving E1 activating enzymes, E2 conjugating enzymes, and E3 ligases (1). Chain formation can proceed in the same manner by repetitively adding ubiquitins to one or more of seven lysines on conjugated ubiquitin, potentially generating ubiquitin chains of several different topologies (2, 3). The linkage, topology, and length of the ubiquitin chains are thought to determine the fate of the tagged protein: K48-linked ubiquitin for degradation and K63 for signaling DNA damage and inflammation (4).We have studied the linkage and topology of ubiquitin chains generated by the APC, a multisubunit E3 enzyme that controls cell-cycle progression (5). Recently, two interesting observations have been made about chain topology: First, different E2s might be required in concert to form long ubiquitin conjugates on APC substrates (6). Second, the density of ubiquitin, rather than the length of the chains, may qualify substrates for degradation (7).Like most E3 ligases, APC modifies multiple lysine residues on each substrate, generating a diverse mixture of products. Poor resolution obtained in sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) hinders analysis. Even when distinct bands are observed, they may not correspond to single products. A band of a discrete molecular weight may reflect ubiquitination on multiple lysine residues or, alternatively, the formation of ubiquitin chains on single-lysine sites.Dissecting the topology of the ubiquitin chains requires a careful simplification of the ubiquitination reaction under meaningful conditions. To achieve that, following earlier work of Petroski and Deshaies (8), we have modified the well-characterized APC substrate, securin, and generated a model substrate that has only a single-lysine residue available for ubiquitination, thereby limiting chain formation to a single chain. By using this model substrate, we discovered that the ubiquitin conjugates formed on APC substrates are preferentially linked through ubiquitin lysine 11. Similar results have r...

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The Ubiquitin-Conjugating Enzyme E2-EPF Is Overexpressed in Primary Breast Cancer and Modulates Sensitivity to Topoisomerase II Inhibition

Cited by 47 publications

References 18 publications

UBE2S is associated with malignant characteristics of breast cancer cells

UBE2S is associated with malignant characteristics of breast cancer cells

Identification of a physiological E2 module for the human anaphase-promoting complex

UBE2S drives elongation of K11-linked ubiquitin chains by the Anaphase-Promoting Complex

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