A Diverse Family of Proteins Containing Tumor Necrosis Factor Receptor-associated Factor Domains

Zapata, Juán M.; Pawłowski, Krzysztof; Haas, Elvira; Ware, Carl F.; Godzik, Adam; Reed, John C.

doi:10.1074/jbc.m100354200

Cited by 202 publications

(157 citation statements)

References 74 publications

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“…Recruitment of USP7 to TRAFs might be expected to interfere with NF-kB activation by preventing I-kB degradation resulting from polyubiquination. In support of this USP7 inhibits NF-kB induction caused by transient over-expression of TRAF2 and/or TRAF6 (Zapata et al, 2001). However, expression of a TRAF domaincontaining region of USP7 in the absence of its ubiquitin-protease domain is more inhibitory than full-length USP7.…”

Section: Role Of Traf2 In Nf-kb Activationmentioning

confidence: 95%

Tumor necrosis factor receptor-associated factors (TRAFs)

2001

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Section: Role Of Traf2 In Nf-kb Activationmentioning

confidence: 95%

Tumor necrosis factor receptor-associated factors (TRAFs)

2001

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“…This example suggests a mechanism that may be more generally relevant to other ubiquitin E3 ligases of the RING finger or other classes. Indeed, brca1 has been reported to interact with the ubiquitin protease BAP1 (52), and several members of the TRAF protein family are themselves RING finger E3 ligases that interact with USP7 (39). Because autoubiquitination appears to play an important role in the regulation of TRAF2, TRAF3, and TRAF6 activity (46 -48), the potential of these proteins to interact with USP7 could in principle provide another means of regulating TRAF-mediated signaling.…”

Section: Discussionmentioning

confidence: 99%

A RING Finger Ubiquitin Ligase Is Protected from Autocatalyzed Ubiquitination and Degradation by Binding to Ubiquitin-specific Protease USP7

Canning

Boutell

Parkinson

et al. 2004

Journal of Biological Chemistry

128

122

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Herpes simplex virus type 1 immediate-early regulatory protein ICP0 stimulates lytic infection and reactivation from latency, processes that require the ubiquitin E3 ligase activity mediated by the RING finger domain in the N-terminal portion of the protein. ICP0 stimulates the production of polyubiquitin chains by the ubiquitin-conjugating enzymes UbcH5a and UbcH6 in vitro, and in infected and transfected cells it induces the proteasome-dependent degradation of a number of cellular proteins including PML, the major constituent protein of PML nuclear bodies. However, ICP0 binds strongly to the cellular ubiquitin-specific protease USP7, a member of a family of proteins that cleave polyubiquitin chains and/or ubiquitin precursors. The region of ICP0 that is required for its interaction with USP7 has been mapped, and mutations in this domain reduce the functionality of ICP0. These findings pose the question: why does ICP0 include domains that are associated with the potentially antagonistic functions of ubiquitin conjugation and deconjugation? Here we report that although neither protein affected the intrinsic activities of the other in vitro, USP7 protected ICP0 from autoubiquitination in vitro, and their interaction can greatly increase the stability of ICP0 in vivo. These results demonstrate that RING finger-mediated autoubiquitination of ICP0 is biologically relevant and can be regulated by interaction with USP7. This principle may extend to a number of cellular RING finger E3 ubiquitin ligase proteins that have analogous interactions with ubiquitin-specific cleavage enzymes.Herpes simplex virus type 1 (HSV-1) 1 is a common human pathogen that can establish a lifelong quiescent infection in sensory neurons following primary infection of epithelial cells. Environmental stimuli such as stress and sunlight trigger periodic recurrences of lytic infection, causing cold sores and genital lesions. HSV-1 expresses three broad groups of temporally regulated genes during lytic infection, termed immediate-early (IE), early, and late (for reviews, see Refs. 1 and 2). The IE protein ICP0 has an important role in the mechanisms that govern the switch between lytic and latent infection (reviewed in Refs. 3-5). Although not essential for viral replication, ICP0 increases the probability of the virus entering lytic infection, particularly after low multiplicity infection of human fibroblasts, and in its absence, viral genomes are more likely to become repressed and establish a quiescent infection (5-7). ICP0 stimulates the expression of all three classes of viral genes by as yet uncertain mechanisms that correlate with its ability to induce the degradation of a number of cellular proteins (8 -12). ICP0 includes a zinc-binding RING finger domain in its N-terminal portion, and in its C-terminal third lie a nuclear localization signal and motifs required for self-multimerization and efficient localization at specific nuclear substructures known as ND10 or PML nuclear bodies. Consistent with its ability to induce the degradation of...

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“…15,16 To further identify the initiating pathway of apoptosis, caspase activity assay and Western blot for regulators of apoptosis were performed. As shown in Figure 2b, the activity of caspase-3 and caspase-9 but not caspase-8 was increased.…”

Section: Sk228 Induces Apoptosis Through the Intrinsic Mitochondrial mentioning

confidence: 99%

The novel indole compound SK228 induces apoptosis and FAK/Paxillin disruption in tumor cell lines and inhibits growth of tumor graft in the nude mouse

Huang

Hsu

Chen

et al. 2011

Intl Journal of Cancer

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Drugs in clinical use with indole structure exhibit side effects. Therefore, to search for indole compounds with more efficacy and less side effect for cancer therapy, we developed a novel indole compound SK228 and examined its effects and mechanisms on antitumor growth and invasion inhibition in cell and tumor xenografts in nude mice models. SK228 significantly inhibited growth of different lung and esophageal cancer cell lines at sub-micromolar range, but not normal lung cells. SK228 induced DNA damages mainly by producing reactive oxygen species (ROS) resulting in apoptosis. SK228 treatment increased the release of cytochrome c into the cytosol along with the increased activity of caspase-3 and -9 without affecting caspase-8, whereas these effects were attenuated by ROS inhibitor. The expression levels of BCL-2 family regulators were also affected. Moreover, low-dose SK228 significantly reduced the invasion of cancer cells. The active phosphorylated form of FAK/Paxillin signaling pathway proteins and active form of RhoA were decreased. Moreover, the F-actin cytoskeleton was disrupted after low-dose SK228 treatment. Growth of an A549 tumor cell xenograft was markedly inhibited without significant side effects. SK228-induced apoptosis was confirmed by terminal deoxynucleotidyl transferase dUTP nick end labeling assay and immunohistochemistry of cleaved caspase-3 in tumors from treated mice. Our study provides the first evidence that SK228 exhibits cancer cell-specific cytotoxicity by inducing mitochondria-mediated apoptosis. In addition, SK228 inhibits cancer cell invasion via FAK/Paxillin disruption at noncytotoxic doses. SK228 can be further tested as a pharmaceutical compound for cancer treatment.There are three standard therapies for cancer treatment including surgery, radiotherapy and chemotherapy. Chemotherapy has a role either as strategic treatment for locally advanced disease or as a palliative treatment for metastatic tumors. 1,2 However, clinical use of chemotherapy is still unsatisfactory due to limited response rate, small survival benefit and poor prognosis. Therefore, the development of novel anticancer drug, which is more effective and shows less side effect for cancer patients, is urgently needed.Several studies have indicated that compounds containing indole structure are highly cytotoxic against many tumoral cell lines, and the indole ring seems to be the core nucleus of several potent tubulin polymerization inhibitors. 3 The most wildly used clinical antimicrotubule drugs containing indole structure is Vinca alkaloids. They are also known as microtubule-destabilizing agents, which includes natural compound vinblastine, vincristine and two semisynthetic derivatives, vindesine and vinorelbine. 4 Several new compounds containing indole structure isolated from natural sources or synthesized were shown to have high potential for cancer treatment. For example, indole-3-carbinol (I3C) was isolated from cruciferous vegetables with high potential for cancer therapy. I3C and its metabolites inhibited ...

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A Diverse Family of Proteins Containing Tumor Necrosis Factor Receptor-associated Factor Domains

Cited by 202 publications

References 74 publications

Tumor necrosis factor receptor-associated factors (TRAFs)

Tumor necrosis factor receptor-associated factors (TRAFs)

A RING Finger Ubiquitin Ligase Is Protected from Autocatalyzed Ubiquitination and Degradation by Binding to Ubiquitin-specific Protease USP7

The novel indole compound SK228 induces apoptosis and FAK/Paxillin disruption in tumor cell lines and inhibits growth of tumor graft in the nude mouse

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