Oncoprotein p28 GANK binds to RelA and retains NF-kappaB in the cytoplasm through nuclear export.
p28(GANK) (also known as PSMD10, p28 and gankyrin) is an ankyrin repeat anti-apoptotic oncoprotein that is commonly overexpressed in hepatocellular carcinomas and increases the degradation of p53 and Rb. NF-kappaB (nuclear factor-kappaB) is known to be sequestered in the cytoplasm by I kappaB (inhibitor of NF-kappaB) proteins, but much less is known about the cytoplasmic retention of NF-kappaB by other cellular proteins. Here we show that p28(GANK) inhibits NF-kappaB activity. As a nuclear-cytoplasmic shuttling protein, p28(GANK) directly binds to NF-kappaB/RelA and exports RelA from nucleus through a chromosomal region maintenance-1 (CRM-1) dependent pathway, which results in the cytoplasmic retention of NF-kappaB/RelA. We demonstrate that all the ankyrin repeats of p28(GANK) are required for the interaction with RelA and that the N terminus of p28(GANK), which contains the nuclear export sequence (NES), is responsible for suppressing NF-kappaB/RelA nuclear translocation. These results suggest that overexpression of p28(GANK) prevents the nuclear localization and inhibits the activity of NF-kappaB/RelA.
International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Shanghai 200438, China.
Yao
Y
Chen
Hong Hai
HH
Li
Jing
J
Fu
Xue Feng
XF
Wang
Yi Bin
YB
Ren
Li Wei
LW
Dong
Shan Hua
SH
Tang
Shu Qing
SQ
Liu
Meng Chao
MC
Wu
Hong Yang
HY
Wang
D021581:Active Transport, Cell Nucleus; D017089:Ankyrin Repeat; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D049790:Nuclear Export Signals; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051996:Transcription Factor RelA / Q000378:metabolism*
D016328:NF-kappa B; D049790:Nuclear Export Signals; C403591:PSMD10 protein, human; D011518:Proto-Oncogene Proteins; C498143:RELA protein, human; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D046988:Proteasome Endopeptidase Complex