Regulation of hematopoiesis by the K63-specific ubiquitin-conjugating enzyme Ubc13

Wu, Xuefeng; Yamamoto, Masahiro; Akira, Shizuo; Sun, Shao Cong

doi:10.1073/pnas.0906547106

Cited by 31 publications

(30 citation statements)

References 37 publications

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“…50 One concern for targeting Ubc13 are the potential side effects that it may generate, because Ubc13 is involved in multiple signaling pathways and has been shown to play crucial roles in mouse embryo development and hematopoiesis. 25,51 Interestingly, NSC697923 (and knockdown of Ubc13) has much less toxic effects on the proliferation and survival of several other types of cells, such as breast cancer and osteosarcoma cells, compared with its effect on DLBCL cells (supplemental Figure 6 and data not shown). It thus appears that not all cells depend on Ubc13 for survival, thereby providing a potential opportunity to target this E2 enzyme in DLBCL with tolerable side effects.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of proliferation and survival of diffuse large B-cell lymphoma cells by a small-molecule inhibitor of the ubiquitin-conjugating enzyme Ubc13-Uev1A

Pulvino¹,

Ye²,

Oleksyn

et al. 2012

Blood

128

119

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IntroductionDiffuse large B-cell lymphoma (DLBCL) is an aggressive and heterogeneous disease comprising at least 3 major subtypes with distinct molecular, biologic, and clinical properties: activated B cell-like DLBCL (ABC-DLBCL), germinal center B cell-like DLBCL (GCB-DLBCL), and primary mediastinal B-cell lymphoma. 1,2 Although the overall cure rate for DLBCL reaches more than 50% with the current therapies such as R-CHOP (rituximab plus cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone/prednisolone), less than 40% of ABC-DLBCL patients are cured. [2][3][4] Therefore, new therapy approaches efficient for this and other DLBCL subtypes are highly desirable.The transcription factor NF-B controls the expression of a wide range of genes involved in cell proliferation, survival, stress response, angiogenesis, and inflammation. 5,6 NF-B activity is tightly regulated by multiple signaling pathways, and abnormal NF-B activation has been linked to cancer development and progression. [7][8][9] Constitutive NF-B activation has been observed in high frequency in all of the main DLBCL subtypes, especially in ABC-DLBCL, with more than 90% of the tumors showing nuclear NF-B, the hallmark of its activation. 9-14 A recent genomic study revealed that more than 60% of ABC-DLBCLs and approximately 30% of GCB-DLBCLs harbor somatic mutations in multiple components of NF-B signaling pathways, such as the BCR, CD40, and TLR pathways. 15 Significantly, it has been demonstrated that constitutive NF-B signaling is required for the proliferation and survival of ABC-DLBCL cell lines. 11,13,16,17 All of these observations suggest a primary role for constitutive NF-B signaling in the pathogenesis of DLBCL and, therefore, the NF-B signaling pathway may represent a rational therapeutic target in DLBCL. 9,11,18 Ubiquitination, the covalent attachment of the ubiquitin (Ub) molecule to target proteins, regulates diverse cellular processes. 19 Ubiquitination proceeds through a stepwise enzymatic cascade involving 3 classes of enzymes: a Ub-activating enzyme (E1), a Ub-conjugating enzyme (E2), and a Ub ligase (E3). The E1 enzyme activates Ub in an ATP-dependent manner and transfers the activated Ub to an E2 enzyme through the formation of a thioester bond between the carboxy terminus of Ub and the active site cysteine of the E2, generating an E2 and Ub thioester conjugate (referred to as E2ϳUb). The E2 then cooperates with an E3 to attach the Ub to a lysine residue of a substrate. Ub itself can serve as a substrate and the process can undergo multiple rounds, resulting in the formation of polyubiquitin chains. 19,20 Because Ub has 7 lysine residues and any one of them can be conjugated to another Ub, polyubiquitin chains of different linkages with distinct functional properties are formed in cells. For example, lysine 48 (K48)-linked polyubiquitin chains typically target substrates for proteasomal degradation, whereas K63-linked polyubiquitin chains function as scaffolds to assemble protein complexes in NF-B signaling and DNA repair. [...

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Section: Discussionmentioning

confidence: 99%

Inhibition of proliferation and survival of diffuse large B-cell lymphoma cells by a small-molecule inhibitor of the ubiquitin-conjugating enzyme Ubc13-Uev1A

Pulvino¹,

Ye²,

Oleksyn

et al. 2012

Blood

128

119

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“…Ubc13 functions in a dimeric complex with the non-catalytic E2 variant Uev1A or Mms2 (Hofmann and Pickart, 1999;Deng et al, 2000;Eddins et al, 2006). In mice, knockout of Ubc13 results in early embryonic lethality, and conditional knockout in myeloid cells or heterozygosity produces defects in the immune response and hematopoiesis (Yamamoto et al, 2006;Fukushima et al, 2007;Wu et al, 2009). In C. elegans, UEV-1 is involved in the trafficking of glutamate receptor GLR-1 in neurons (Kramer et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Fertilization-induced K63-linked ubiquitylation mediates clearance of maternal membrane proteins

et al. 2014

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In Caenorhabditis elegans, fertilization triggers endocytosis and rapid turnover of maternal surface membrane proteins in lysosomes, although the precise mechanism of this inducible endocytosis is unknown. We found that high levels of K63-linked ubiquitin chains transiently accumulated on endosomes upon fertilization. Endocytosis and the endosomal accumulation of ubiquitin were both regulated downstream of the anaphase-promoting complex, which drives the oocyte's meiotic cell cycle after fertilization. The clearance of maternal membrane proteins and the accumulation of K63-linked ubiquitin on endosomes depended on UBC-13 and UEV-1, which function as an E2 complex that specifically mediates chain elongation of K63-linked polyubiquitin. CAV-1-GFP, an endocytic cargo protein, was modified with K63-linked polyubiquitin in a UBC-13/UEV-1-dependent manner. In ubc-13 or uev-1 mutants, CAV-1-GFP and other membrane proteins were internalized from the plasma membrane normally after fertilization. However, they were not efficiently targeted to the multivesicular body (MVB) pathway but recycled to the cell surface. Our results suggest that UBC-13-dependent K63-linked ubiquitylation is required for proper MVB sorting rather than for internalization. These results also demonstrate a developmentally controlled function of K63-linked ubiquitylation.

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“…26 An in vivo role of K63-Ub in early stages of hematopoiesis has been previously suggested based on the observation that the loss of Ubc13 (the Ub-conjugating enzyme specific for K63-Ub chains) in mice leads to hematopoietic failure owing to loss of HSCs and progenitor cells (HSPCs). 27 However, how K63-Ub affects hematopoiesis or HSC function has not been well established.…”

Section: /2mentioning

confidence: 99%

MERIT40 deficiency expands hematopoietic stem cell pools by regulating thrombopoietin receptor signaling

Rozenova

Jiang

Donaghy

et al. 2015

Blood

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Regulation of hematopoiesis by the K63-specific ubiquitin-conjugating enzyme Ubc13

Cited by 31 publications

References 37 publications

Inhibition of proliferation and survival of diffuse large B-cell lymphoma cells by a small-molecule inhibitor of the ubiquitin-conjugating enzyme Ubc13-Uev1A

Inhibition of proliferation and survival of diffuse large B-cell lymphoma cells by a small-molecule inhibitor of the ubiquitin-conjugating enzyme Ubc13-Uev1A

Fertilization-induced K63-linked ubiquitylation mediates clearance of maternal membrane proteins

MERIT40 deficiency expands hematopoietic stem cell pools by regulating thrombopoietin receptor signaling

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