AGE-RAGE signal generates a specific NF-?B RelA "barcode" that directs collagen I expression.
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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-?B, leading to inflammation. A large number of stimuli can activate NF-?B; yet different stimuli, or the same stimulus for NF-?B in different cellular settings, produce a very different transcriptional landscape and physiological outcome. The NF-?B barcode hypothesis posits that cellular network dynamics generate signal-specific post-translational modifications, or a "barcode" to NF-?B, and that a signature "barcode" mediates a specific gene expression pattern. In the current study, we established that AGE-RAGE signaling results in NF-?B 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-?B activation, and aging-associated arterial alterations in structure and function.
SUBMITTER: Peng Y
PROVIDER: S-EPMC4700418 | biostudies-literature | 2016 Jan
REPOSITORIES: biostudies-literature
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