期刊
JOURNAL OF INVESTIGATIVE DERMATOLOGY
卷 139, 期 2, 页码 333-341出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jid.2018.07.044
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类别
资金
- JSPS KAKENHI
- Joint Usage/Research Center Institute for Genetic Medicine, Hokkaido University
- Takeda Science Foundation
- Institute for Fermentation Osaka
- Mitsubishi Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Tokyo Medical Research Foundation
Keloids mark a chronic inflammatory disease characterized by a fibroproliferative disorder of the skin. A genome-wide association study showed that single-nucleotide polymorphism rs8032158 in the neural precursor cell-expressed NEDD4 gene, which has six protein-coding transcript variants (TVs), is genetically linked to keloids. Here, we show that the high frequency of risk allele C in rs8032158 in keloid patients is associated with a selectively higher expression of TV3 of NEDD4 to activate the NF-kB pathway. Comparisons of keloid scars with normal skin samples that do not have the single-nucleotide polymorphism allele and were derived from different anatomical sites showed stronger expressions of NEDD4 TV3 and activated forms of NF-kB and STAT3 in keloid scars. Forced expression or selective knockdown of NEDD4 TV3 increased or decreased NF-kB activation in vitro. Furthermore, NEDD4 knockdown suppressed NF-kBedependent inflammation development in vivo. Mechanistic analysis showed that NEDD4 TV3 is involved in NF-kB activation through its association with the adaptor protein RIP. These results suggest that NEDD4 TV3 is a potential diagnostic marker and therapeutic target for chronic skin diseases, including keloid.
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