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Peptides genetically selected for NF-?B activation cooperate with oncogene Ras and model carcinogenic role of inflammation.

ABSTRACT: Chronic inflammation is associated with increased cancer risk. Furthermore, the transcription factor NF-?B, a central regulator of inflammatory responses, is constitutively active in most tumors. To determine whether active NF-?B inherently contributes to malignant transformation, we isolated a set of NF-?B-activating genetic elements and tested their oncogenic potential in rodent cell transformation models. Genetic elements with desired properties were isolated using biologically active selectable peptide technology, which involves functional screening of lentiviral libraries encoding 20 or 50 amino acid-long polypeptides supplemented with endoplasmic reticulum-targeting and oligomerization domains. Twelve NF-?B-activating selectable peptides (NASPs) representing specific fragments of six proteins, none of which was previously associated with NF-?B activation, were isolated from libraries of 200,000 peptides derived from 500 human extracellular proteins. Using selective knockdown of distinct components of the NF-?B pathway, we showed that the isolated NASPs act either via or upstream of TNF receptor-associated factor 6. Transduction of NASPs into mouse and rat embryo fibroblasts did not, in itself, alter their growth. However, when coexpressed with oncogenic Ras (H-Ras(V12)), NASPs allowed rodent fibroblasts to overcome H-Ras(V12)-mediated p53-dependent senescence and acquire a transformed tumorigenic phenotype. Consistent with their ability to cooperate with oncogenic Ras in cell transformation, NASP expression reduced the transactivation activity of p53. This system provides an in vitro model of NF-?B-driven carcinogenesis and suggests that the known carcinogenic effects of inflammation may be at least partially due to NF-?B-mediated abrogation of oncogene-induced senescence.

SUBMITTER: Natarajan V

PROVIDER: S-EPMC3910623 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Peptides genetically selected for NF-κB activation cooperate with oncogene Ras and model carcinogenic role of inflammation.

Natarajan Venkatesh V Komarov Andrei P AP Ippolito Thomas T Bonneau Kyle K Chenchik Alex A AA Gudkov Andrei V AV

Proceedings of the National Academy of Sciences of the United States of America 20140113 4

Chronic inflammation is associated with increased cancer risk. Furthermore, the transcription factor NF-κB, a central regulator of inflammatory responses, is constitutively active in most tumors. To determine whether active NF-κB inherently contributes to malignant transformation, we isolated a set of NF-κB-activating genetic elements and tested their oncogenic potential in rodent cell transformation models. Genetic elements with desired properties were isolated using biologically active selecta ...[more]

PMID: 24474797

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Project description:Elevations in plasma levels of pro-inflammatory cytokines and C-reactive protein (CRP) in patient blood have been associated with impairments in cognitive abilities and more severe psychiatric symptoms in people with schizophrenia. The transcription factor nuclear factor kappa B (NF-κB) regulates the gene expression of pro-inflammatory factors whose protein products trigger CRP release. NF-κB activation pathway mRNAs are increased in the brain in schizophrenia and are strongly related to neuroinflammation. Thus, it is likely that this central immune regulator is also dysregulated in the blood and associated with cytokine and CRP levels. We measured levels of six pro-inflammatory cytokine mRNAs and 18 mRNAs encoding NF-κB pathway members in peripheral blood leukocytes from 87 people with schizophrenia and 83 healthy control subjects. We then assessed the relationships between the alterations in NF-κB pathway genes, pro-inflammatory cytokine and CRP levels, psychiatric symptoms and cognition in people with schizophrenia. IL-1β and IFN-γ mRNAs were increased in patients compared to controls (both p < 0.001), while IL-6, IL-8, IL-18, and TNF-α mRNAs did not differ. Recursive two-step cluster analysis revealed that high levels of IL-1β mRNA and high levels of plasma CRP defined 'high inflammation' individuals in our cohort, and a higher proportion of people with schizophrenia were identified as displaying 'high inflammation' compared to controls using this method (p = 0.03). Overall, leukocyte expression of the NF-κB-activating receptors, TLR4 and TNFR2, and the NF-κB subunit, RelB, was increased in people with schizophrenia compared to healthy control subjects (all p < 0.01), while NF-κB-inducing kinase mRNAs IKKβ and NIK were downregulated in patients (all p < 0.05). We found that elevations in TLR4 and RelB appear more related to inflammatory status than to a diagnosis of schizophrenia, but changes in TNFR2 occur in both the high and low inflammation patients (but were exaggerated in high inflammation patients). Further, decreased leukocyte expression of IKKβ and NIK mRNAs was unique to high inflammation patients, which may represent schizophrenia-specific dysregulation of NF-κB that gives rise to peripheral inflammation in a subset of patients.

Dataset Information

Peptides genetically selected for NF-?B activation cooperate with oncogene Ras and model carcinogenic role of inflammation.

Publications

Peptides genetically selected for NF-κB activation cooperate with oncogene Ras and model carcinogenic role of inflammation.

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