RNA-Seq and ChIP-Seq reveal SQSTM1/p62 as a key mediator of JunB suppression of NF-κB-dependent inflammation.

dc.contributor.author

Zhang, Xiaoling

dc.contributor.author

Jin, Jane Y

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Wu, Joseph

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Qin, Xiaoxia

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Streilein, Robert

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Hall, Russell P

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Zhang, Jennifer Y

dc.coverage.spatial

United States

dc.date.accessioned

2017-08-02T13:58:40Z

dc.date.available

2017-08-02T13:58:40Z

dc.date.issued

2015-04

dc.description.abstract

Mice with epidermal deletion of JunB transcription factor displayed a psoriasis-like inflammation. The relevance of these findings to humans and the mechanisms mediating JunB function are not fully understood. Here we demonstrate that impaired JunB function via gene silencing or overexpression of a dominant negative mutant increased human keratinocyte cell proliferation but decreased cell barrier function. RNA-seq revealed over 500 genes affected by JunB loss of function, which included the upregulation of an array of proinflammatory molecules relevant to psoriasis. Among these were tumor necrosis factor α (TNFα), CCL2, CXCL10, IL6R, and SQSTM1, an adaptor protein involved in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. Chromatin immunoprecipitation (ChIP)-Seq and gene reporter analyses showed that JunB directly suppressed SQSTM1 by binding to a consensus AP-1 cis element located around 2 kb upstream of SQSTM1-transcription start site. Similar to JunB loss of function, SQSTM1-overexpression induced TNFα, CCL2, and CXCL10. Conversely, NF-κB inhibition genetically with a mutant IκBα or pharmacologically with pyrrolidine dithiocarbamate (PDTC) prevented cytokine, but not IL6R, induction by JunB deficiency. Taken together, our findings indicate that JunB controls epidermal growth, barrier formation, and proinflammatory responses through direct and indirect mechanisms, pinpointing SQSTM1 as a key mediator of JunB suppression of NF-κB-dependent inflammation.

dc.identifier

https://www.ncbi.nlm.nih.gov/pubmed/25501661

dc.identifier

S0022-202X(15)37204-3

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1523-1747

dc.identifier.uri

https://hdl.handle.net/10161/15166

dc.language

eng

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Nature Publishing Group

dc.relation.ispartof

J Invest Dermatol

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10.1038/jid.2014.519

dc.subject

Adaptor Proteins, Signal Transducing

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Animals

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Cell Adhesion

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Cell Proliferation

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Chemokine CCL2

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Chemokine CXCL10

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Chromatin Immunoprecipitation

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Cytokines

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Epidermis

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Gene Deletion

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Genes, Reporter

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HEK293 Cells

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Heat-Shock Proteins

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Humans

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Inflammation

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Keratinocytes

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Mice

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Mutation

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NF-kappa B

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Oligonucleotide Array Sequence Analysis

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Pyrrolidines

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Regeneration

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Sequence Analysis, RNA

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Sequestosome-1 Protein

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Skin Physiological Phenomena

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Thiocarbamates

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Transcription Factors

dc.title

RNA-Seq and ChIP-Seq reveal SQSTM1/p62 as a key mediator of JunB suppression of NF-κB-dependent inflammation.

dc.type

Journal article

duke.contributor.orcid

Hall, Russell P|0000-0001-7621-4935

duke.contributor.orcid

Zhang, Jennifer Y|0000-0002-4485-1750

pubs.author-url

https://www.ncbi.nlm.nih.gov/pubmed/25501661

pubs.begin-page

1016

pubs.end-page

1024

pubs.issue

4

pubs.organisational-group

Basic Science Departments

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Clinical Science Departments

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Dermatology

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Duke

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Duke Cancer Institute

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Immunology

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Institutes and Centers

pubs.organisational-group

Pathology

pubs.organisational-group

School of Medicine

pubs.publication-status

Published

pubs.volume

135

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