NF-κB as a Target for Oncogenic Viruses

Sun, Shao Cong; Cesarman, Ethel

doi:10.1007/82_2010_108

Cited by 42 publications

(48 citation statements)

References 281 publications

(347 reference statements)

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“…KSHV is tightly associated with Kaposi's sarcoma, a cancer commonly seen in individuals infected with the human immunodeficiency virus [99]. In addition, KSHV is also found in several lymphoproliferative disorders, such as primary effusion lymphoma.…”

Section: Persistent Activation By Oncogenic Viruses and Bacteriamentioning

confidence: 99%

“…KSHV encodes a viral homolog of the cellular FLICE inhibitor protein (FLIP), termed vFLIP, which functions as an anti-apoptotic protein. Like HTLV1 Tax, vFLIP stimulates both the canonical and non-canonical NF-κB pathway via a mechanism that involves interaction with IKKγ [99]. Binding of vFLIP to IKKγ induces the conversion of IKKγ from a helical bundle conformation to an open conformation, which is thought to contribute to the activation of IKK catalytic subunits [100].…”

Section: Persistent Activation By Oncogenic Viruses and Bacteriamentioning

confidence: 99%

“…However, accumulating evidence suggests that EBV may be associated with certain forms of lymphomas under immunodeficient conditions [99]. EBV-encoded LMP1 protein is a major viral activator of NF-κB that targets both the canonical and non-canonical pathways.…”

Section: Persistent Activation By Oncogenic Viruses and Bacteriamentioning

confidence: 99%

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Non-canonical NF-κB signaling pathway

2010

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The non-canonical NF-κB pathway is an important arm of NF-κB signaling that predominantly targets activation of the p52/RelB NF-κB complex. This pathway depends on the inducible processing of p100, a molecule functioning as both the precursor of p52 and a RelB-specific inhibitor. A central signaling component of the non-canonical pathway is NF-κB-inducing kinase (NIK), which integrates signals from a subset of TNF receptor family members and activates a downstream kinase, IκB kinase-α (IKKα), for triggering p100 phosphorylation and processing. A unique mechanism of NIK regulation is through its fate control: the basal level of NIK is kept low by a TRAF-cIAP destruction complex and signal-induced non-canonical NF-κB signaling involves NIK stabilization. Tight control of the fate of NIK is important, since deregulated NIK accumulation is associated with lymphoid malignancies.

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Section: Persistent Activation By Oncogenic Viruses and Bacteriamentioning

confidence: 99%

Section: Persistent Activation By Oncogenic Viruses and Bacteriamentioning

confidence: 99%

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Non-canonical NF-κB signaling pathway

2010

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“…Many viruses have been shown to target NF-B pathways to evade innate immune responses. On the other hand, accumulated studies have revealed that activation of NF-B signaling is induced and incorporated in the viral life cycle and is important for pathogenicity of oncogenic viruses such as Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), and human adult T cell leukemia virus 1 (HTLV-1) (16).…”

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confidence: 99%

Activation of NF-κB by Human Papillomavirus 16 E1 Limits E1-Dependent Viral Replication through Degradation of E1

Nakahara

Tanaka

Ohno

et al. 2015

J Virol

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NF-B is a family of transcription factors that regulate gene expression involved in many processes, such as the inflammatory response and cancer progression. Little is known about associations of NF-B with the human papillomavirus (HPV) life cycle. We have developed a tissue culture system to conditionally induce E1-dependent replication of the human papillomavirus 16 (HPV16) genome in human cervical keratinocytes and found that expression of HPV16 E1, a viral helicase, results in reduction of IB␣ and subsequent activation of NF-B in a manner dependent on helicase activity. Exogenous expression of a degradation-resistant mutant of IB␣, which inhibits the activation of NF-B, enhanced E1-dependent replication of the viral genome. Wortmannin, a broad inhibitor of phosphoinositide 3-kinases (PI3Ks), and, to a lesser extent, VE-822, an ATR kinase inhibitor, but not KU55933, an ATM kinase inhibitor, suppressed the activation of NF-B and augmented E1-dependent replication of the HPV16 genome. Interestingly, the enhancement of E1-dependent replication of the viral genome was associated with increased stability of E1 in the presence of wortmannin as well as the IB␣ mutant. Collectively, we propose that expression of E1 induces NF-B activation at least in part through the ATR-dependent DNA damage response and that NF-B in turn limits E1-dependent replication of HPV16 through degradation of E1, so that E1 and NF-B may constitute a negative feedback loop. IMPORTANCE A major risk factor in human papillomavirus (HPV)-associated cancers is persistent infection with high-risk HPVs. To eradicate viruses from infected tissue, it is important to understand molecular mechanisms underlying the establishment and maintenance of persistent infection. In this study, we obtained evidence that human papillomavirus 16 (HPV16) E1, a viral DNA helicase essential for amplification of the viral genomes, induces NF-B activation and that this limits E1-dependent genome replication of HPV16. These results suggest that NF-B mediates a negative feedback loop to regulate HPV replication and that this feedback loop could be associated with control of the viral copy numbers. We could thus show for the first time that NF-B activity is involved in the establishment and maintenance of persistent HPV infection. Human papillomaviruses (HPVs) are a large family of nonenveloped, small DNA viruses with an approximately 8-kbp double-stranded circular genome that infect stratified squamous epithelium in various anatomical sites such as skin, the anogenital tract, and the oral cavity. Virus infection can cause hyperproliferative lesions, ranging from verrucae to cancer. To date, at least 180 types of HPVs have been cloned from clinical lesions and classified as either cutaneous or mucosal types based on their predilection for different sites of infection. A subset of mucosal HPVs, high-risk HPVs (HR-HPVs), such as HPV16, are strongly associated with anogenital cancers, including nearly 100% of cervical cancers and some proportion of head and neck cancers...

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“…The underlying mechanism is still unknown. Several viruses have been demonstrated to interfere with the NF-B pathway (32,33); for instance, HTLV1 is known to activate the IKK complex by direct binding of its transforming protein, Tax, to IKK␥ (34). Preliminary studies from our group have shown that, similarly to Tax, HPV38 E7 can bind to IKK␤ (D. Saidj, unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Oncoprotein E7 from Beta Human Papillomavirus 38 Induces Formation of an Inhibitory Complex for a Subset of p53-Regulated Promoters

Saidj

Cros

Hernandez-Vargas

et al. 2013

J Virol

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bOur previous studies on cutaneous beta human papillomavirus 38 (HPV38) E6 and E7 oncoproteins highlighted a novel activity of IB kinase beta (IKK␤) in the nucleus of human keratinocytes, where it phosphorylates and stabilizes ⌬Np73␣, an antagonist of p53/p73 functions. Here, we further characterize the role of the IKK␤ nuclear form. We show that IKK␤ nuclear translocation and ⌬Np73␣ accumulation are mediated mainly by HPV38 E7 oncoprotein. Chromatin immunoprecipitation (ChIP)/Re-ChIP experiments showed that ⌬Np73␣ and IKK␤ are part, together with two epigenetic enzymes DNA methyltransferase 1 (DNMT1) and the enhancer of zeste homolog 2 (EZH2), of a transcriptional regulatory complex that inhibits the expression of some p53-regulated genes, such as PIG3. Recruitment to the PIG3 promoter of EZH2 and DNMT1 resulted in trimethylation of histone 3 on lysine 27 and in DNA methylation, respectively, both events associated with gene expression silencing. Decreases in the intracellular levels of HPV38 E7 or ⌬Np73␣ strongly affected the recruitment of the inhibitory transcriptional complex to the PIG3 promoter, with consequent restoration of p53-regulated gene expression. Finally, the ⌬Np73␣/IKK␤/DNMT1/EZH2 complex appears to bind a subset of p53-regulated promoters. In fact, the complex is efficiently recruited to several promoters of genes encoding proteins involved in DNA repair and apoptosis, whereas it does not influence the expression of the prosurvival factor Survivin. In summary, our data show that HPV38 via E7 protein promotes the formation of a multiprotein complex that negatively regulates the expression of several p53-regulated genes.

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NF-κB as a Target for Oncogenic Viruses

Cited by 42 publications

References 281 publications

Non-canonical NF-κB signaling pathway

Non-canonical NF-κB signaling pathway

Activation of NF-κB by Human Papillomavirus 16 E1 Limits E1-Dependent Viral Replication through Degradation of E1

Oncoprotein E7 from Beta Human Papillomavirus 38 Induces Formation of an Inhibitory Complex for a Subset of p53-Regulated Promoters

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