title: AGE-RAGE signal generates a specific NF-κB RelA "barcode" that directs collagen I expression.
abstract: Advanced glycation end products (AGEs) are sugar-modified biomolecules that accumulate in the body with advancing age, and are implicated in the development of multiple age-associated structural and functional abnormities and diseases. It has been well documented that AGEs signal via their receptor RAGE to activate several cellular programs including NF-κB, leading to inflammation. A large number of stimuli can activate NF-κB; yet different stimuli, or the same stimulus for NF-κB in different cellular settings, produce a very different transcriptional landscape and physiological outcome. The NF-κB barcode hypothesis posits that cellular network dynamics generate signal-specific post-translational modifications, or a "barcode" to NF-κB, and that a signature "barcode" mediates a specific gene expression pattern. In the current study, we established that AGE-RAGE signaling results in NF-κB activation that directs collagen Ia1 and Ia2 expression. We further demonstrated that AGE-RAGE signal induces phosphorylation of RelA at three specific residues, T254, S311, and S536. These modifications are required for transcription of collagen I genes and are a consequence of cellular network dynamics. The increase of collagen content is a hallmark of arterial aging, and our work provides a potential mechanistic link between RAGE signaling, NF-κB activation, and aging-associated arterial alterations in structure and function.
authors.affiliation: Laboratory of Cardiovascular Sciences, National Institute on Aging, National Institute of Health, Baltimore, MD 21224.
authors.forename: Yunqian
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Laboratory of Cardiovascular Sciences, National Institute on Aging, National Institute of Health, Baltimore, MD 21224.
authors.forename: Ji-Min
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Laboratory of Cardiovascular Sciences, National Institute on Aging, National Institute of Health, Baltimore, MD 21224.
authors.forename: Hal-Sol
authors.initials: HS
authors.lastname: Park
authors.affiliation: Laboratory of Cardiovascular Sciences, National Institute on Aging, National Institute of Health, Baltimore, MD 21224.
authors.forename: Annie
authors.initials: A
authors.lastname: Yang
authors.affiliation: Laboratory of Cardiovascular Sciences, National Institute on Aging, National Institute of Health, Baltimore, MD 21224.
authors.forename: Celia
authors.initials: C
authors.lastname: Islam
authors.affiliation: Laboratory of Cardiovascular Sciences, National Institute on Aging, National Institute of Health, Baltimore, MD 21224.
authors.forename: Edward G
authors.initials: EG
authors.lastname: Lakatta
authors.affiliation: Laboratory of Cardiovascular Sciences, National Institute on Aging, National Institute of Health, Baltimore, MD 21224.
authors.forename: Li
authors.initials: L
authors.lastname: Lin
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D024042:Collagen Type I / Q000235:genetics*; D000090602:Collagen Type I, alpha 1 Chain; D005347:Fibroblasts; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D059014:High-Throughput Nucleotide Sequencing; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D009154:Mutation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D051996:Transcription Factor RelA