K63-Linked Ubiquitination in Kinase Activation and Cancer

Wang, Guocan; Gao, Yuan; Li, Liren; Jin, Guoxiang; Zhang, Cai; Chao, Jui I.; Lin, Hui Kuan

doi:10.3389/fonc.2012.00005

Cited by 89 publications

(87 citation statements)

References 198 publications

(257 reference statements)

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“…It has been suggested that TRAF6 induces the activation of IKK complex and TAK1-TAB2 complex via K63-linked polyubiquitin (12-14). TRAF6, an E3 ubiquitin ligase, catalyzes synthesis of K63-linked polyu- biquitination of IKKγ and TRAF6 itself (12). The K63-linked polyubiquitin chains function as a scaffold to recruit the TAK1-TAB2 complex and IKK complex through binding to TAB2 and IKKγ, respectively (13).…”

Section: Discussionmentioning

confidence: 99%

“…RTA, encoded by the immediate-early gene ORF50, is a critical switch molecule for initiating lytic replication. In canonical NF-κB signaling, the NF-κB transcription factor, which is a heterodimer of p50 and p65/RelA, is retained in the cytosol by interaction with IκBα (12). IκBα is further regulated by the IκB kinase (IKK) complex, consisting of IKKα, IKKβ and IKKγ/NEmO.…”

Section: Introductionmentioning

confidence: 99%

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Diallyl trisulfide induces apoptosis by suppressing NF-κB signaling through destabilization of TRAF6 in primary effusion lymphoma

Shigemi

Furukawa

Hosokawa

et al. 2015

International Journal of Oncology

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Abstract. The allyl sulfides, including diallyl sulfide (DAS), diallyl disulfide (DAD), and diallyl trisulfide (DAT), contained in garlic and members of the Allium family, have a variety of pharmacological activities. Therefore, allyl sulfides have been evaluated as potential novel chemotherapeutic agents. Here, we found that DAT inhibited nuclear factor-κB (NF-κB) signaling and induced apoptosis in primary effusion lymphoma (PEL), a subtype of non-Hodgkin's B-cell lymphoma caused by Kaposi's sarcoma-associated herpesvirus (KSHV). We examined the cytotoxic effects of DAS, DAD and DAT on PEL cells. DAT significantly reduced the viability of PEL cells compared with uninfected B-lymphoma cells, and induced the apoptosis of PEL cells by activating caspase-9. DAT induced stabilization of IκBα, and suppressed NF-κB transcriptional activity in PEL cells. We examined the mechanism underlying DAT-mediated IκBα stabilization. The results indicated that DAT stabilized IκBα by inhibiting the phosphorylation of IκBα by the IκB kinase (IKK) complex. Furthermore, DAT induced proteasomal degradation of TRAF6, and DAT suppressed IKKβ-phosphorylation through downregulation of TRAF6. It is known that activation of NF-κB is essential for survival of PEL cells. In fact, the NF-κB inhibitor BAY11-7082 induced apoptosis in PEL cells. In addition, DAT suppressed the production of progeny virus from PEL cells. The administration of DAT suppressed the development of PEL cells and ascites in SCID mice xenografted with PEL cells. These findings provide evidence that DAT has antitumor activity against PEL cells in vitro and in vivo, suggesting it to be a novel therapeutic agent for the treatment of PEL. IntroductionPrimary effusion lymphoma (PEL, also termed body-cavitybased lymphoma) is a malignant B-cell lymphoma caused by Kaposi's sarcoma-associated herpesvirus (KSHV, also named HHV-8) in immunosuppressed individuals, such as AIDS patients or those that have undergone organ transplantation (1,2). PEL is a subtype of non-Hodgkin's lymphoma and is characterized by lymphomatous effusions of pleural and abdominal cavities. KSHV is a rhadinovirus of the γ-herpesvirus subfamily and is closely related to herpesvirus Saimiri and Epstein-Barr virus (EBV). KSHV is the causative agent of Kaposi's sarcoma and AIDS-related lymphoproliferative disorders, such as PEL and multicentric Castleman's disease (3). Similar to other herpesviruses, KSHV has two life cycles (latency and lytic replication). The KSHV genome circularizes and forms a double-stranded DNA, the episome, in the nucleus of PEL cells during latent infection. To establish a latent infection, KSHV expresses several viral genes, including latency-associated nuclear antigen (LANA), v-FLIP, v-cyclin, kaposin and microRNAs, in PEL cells. LANA is required for the replication and maintenance of viral DNA, and contributes to KSHV-associated oncogenesis through interaction with cellular molecules, such as p53, Rb and GSK-3. These viral proteins and RNA manipulate cellular signaling pathways, includ...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Diallyl trisulfide induces apoptosis by suppressing NF-κB signaling through destabilization of TRAF6 in primary effusion lymphoma

Shigemi

Furukawa

Hosokawa

et al. 2015

International Journal of Oncology

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“…Lys 63 -linked ubiquitylation is sometimes required for signaltransduction processes, whereas Lys 48 -linked ubiquitylation typically leads to proteasome degradation (29). Therefore, we created Ub K48-only and K63-only mutants to investigate IpaH4.5-mediated TBK1 ubiquitylation.…”

Section: Ipah45 Induces Tbk1 Degradation By K48-linked Ubiquitinationmentioning

confidence: 99%

Bacterial E3 Ubiquitin Ligase IpaH4.5 of Shigella flexneri Targets TBK1 To Dampen the Host Antibacterial Response

Zheng¹,

Wei²,

Guan³

et al. 2016

The Journal of Immunology

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IFN regulatory factors play a pivotal role in many cellular processes, including inflammatory and immune responses. Their activation is tightly regulated by TANK-binding kinase 1 (TBK1). In response to microbial components, TBK1 activates IFN regulatory factor 3 (IRF3) and cytokine expression. In this article, we show that TBK1 is a novel target of the IpaH4.5 protein, a Shigella type III effector possessing E3 ubiquitin ligase activity. Remarkably, IpaH4.5 interacts with TBK1 and promotes its K48-linked polyubiquitylation. Consequently, polyubiquitylated TBK1 undergoes proteasome-dependent degradation, which perturbs the phosphorylation, nuclear translocation, and activation of IRF3. Because IRF3 and TBK1 are required for restricting Shigella growth, we propose that the polyubiquitylation and degradation of TBK1 during Shigella infection are new bacterial strategies to modulate the host antibacterial responses.

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“…1). The assembly step of activated receptor complexes involves TRAF2 and cellular inhibitor of apoptosis protein 1/2 (cIAP1/2)-mediated K63-linked ubiquitination of several of the components, including TRAF2, TRAF6, TAK1, RIP1, and NF-kB essential modulator (NEMO), which facilitates protein-protein interactions and the assembly of the signaling complexes (10)(11)(12)(13)(14). The main enzyme that removes polyubiquitin chains from the above proteins is the cylindromatosis tumor suppressor cylindromatosis deubiquitinase (Cyld; refs.…”

Section: Interplay Between Nf-kb and Jnk Signaling Pathwaymentioning

confidence: 99%

Molecular Pathways: The Complex Roles of Inflammation Pathways in the Development and Treatment of Liver Cancer

Nikolaou

Sarris

Talianidis

2013

Clinical Cancer Research

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Inflammatory signals from the surrounding microenvironment play important roles in tumor promotion. Key inflammatory mediators and pathways that induce and sustain tumorigenesis have recently been identified in many different cancers. Hepatocellular carcinoma is a paradigm for inflammation-induced cancer, as it most frequently develops in the setting of chronic hepatitis, consecutive cellular damage, and compensatory regeneration. Recent studies revealed that liver damage-mediated inflammation and carcinogenesis are triggered by a complex cross-talk between NF-kB, c-jun-NH 2 -kinase, and STAT3 signaling pathways. Molecular dissection of the mechanisms involved in the interplay between these pathways identified promising new targets for therapeutic intervention. Targeting different components of the signaling cascades may provide efficient means for blocking the apparently irreversible sequence of events initiated by chronic liver inflammation and culminating in liver cancer.

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K63-Linked Ubiquitination in Kinase Activation and Cancer

Cited by 89 publications

References 198 publications

Diallyl trisulfide induces apoptosis by suppressing NF-κB signaling through destabilization of TRAF6 in primary effusion lymphoma

Diallyl trisulfide induces apoptosis by suppressing NF-κB signaling through destabilization of TRAF6 in primary effusion lymphoma

Bacterial E3 Ubiquitin Ligase IpaH4.5 of Shigella flexneri Targets TBK1 To Dampen the Host Antibacterial Response

Molecular Pathways: The Complex Roles of Inflammation Pathways in the Development and Treatment of Liver Cancer

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