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The oncoprotein gankyrin interacts with RelA and suppresses NF-κB activity

2007; Elsevier BV; Volume: 363; Issue: 3 Linguagem: Inglês

10.1016/j.bbrc.2007.09.072

1090-2104

Hiroaki Higashitsuji, Hisako Higashitsuji, Yu Liu, Tomoko Masuda, Takanori Fujita, H. Ismail Abdel-Aziz, Supranee Kongkham, Simon Dawson, R. John Mayer, Yoshito Itoh, Toshiharu Sakurai, Katsuhiko Itoh, Jun Fujita,

Cancer-related molecular mechanisms research

Gankyrin is an oncoprotein commonly overexpressed in hepatocellular carcinomas. It interacts with multiple proteins and accelerates degradation of tumor suppressors Rb and p53. Since gankyrin consists of 7 ankyrin repeats and is structurally similar to IκBs, we investigated its interaction with NF-κB. We found that gankyrin directly binds to RelA. In HeLa and 293 cells, overexpression of gankyrin suppressed the basal as well as TNFα-induced transcriptional activity of NF-κB, whereas down-regulation of gankyrin increased it. Gankyrin did not affect the NF-κB DNA-binding activity or nuclear translocation of RelA induced by TNFα in these cells. Leptomycin B that inhibits nuclear export of RelA suppressed the NF-κB activity, which was further suppressed by gankyrin. The inhibitory effect of gankyrin was abrogated by nicotinamide as well as down-regulation of SIRT1, a class III histone deacetylase. Thus, gankyrin binds to NF-κB and suppresses its activity at the transcription level by modulating acetylation via SIRT1.