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J Neurosci Res. 2017 Jul;95(7):1503-1512. doi: 10.1002/jnr.23959. Epub 2016 Oct 5.

Induction of peptidylarginine deiminase 2 and 3 by dibutyryl cAMP via cAMP-PKA signaling in human astrocytoma U-251MG cells.

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Molecular Regulation of Aging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
Geriatrics and Vascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Research & Development Division, Fujirebio Inc., Tokyo, Japan.
Ilsong Institute of Life Science, Hallym University, Anyang, Gyeonggi-do, Korea.


Peptidylarginine deiminases (PADs) are posttranslational modification enzymes that citrullinate (deiminate) protein arginine residues in a calcium-dependent manner, yielding citrulline residues. Enzymatic citrullination abolishes positive charges of native protein molecules, inevitably causing significant alterations in their structure and function. Previously, we reported the abnormal accumulation of citrullinated proteins and an increase of PAD2 content in hippocampi of patients with Alzheimer disease. In this study, we investigated PAD expression by using dibutyryl cAMP (dbcAMP) in human astrocytoma U-251MG cells. Under normal culture conditions, PAD2 and PAD3 mRNA expression is detectable with quantitative PCR in U-251MG cells. The addition of dbcAMP in a dose-dependent manner significantly increased this mRNA expression and protein levels. Moreover, PAD enzyme activity also increased significantly and dose-dependently. Furthermore, the expression of PAD2 and PAD3 mRNA was inhibited by the cAMP-dependent PKA inhibitor KT5720, suggesting that such expression of dbcAMP-induced PAD2 and PAD3 mRNA is mediated by the cAMP-PKA signaling pathway in U-251MG cells. This is the first report to document the PAD2 and PAD3 mRNA expression induced by dbcAMP and to attribute the induction of these genes to mediation by the cAMP-PKA signaling pathway in U-251MG cells.


PKA; astrocyte; cAMP; citrullinated protein; peptidylarginine deiminase

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