RKIP inhibits NF-kappaB in cancer cells by regulating upstream signaling components of the IkappaB kinase complex.
RKIP was first identified as an inhibitor of the Raf-MEK-ERK signaling pathway. RKIP was also found to play an important role in the NF-kappaB pathway. Genetic and biochemical studies demonstrated that RKIP functioned as a scaffold protein facilitating the phosphorylation of IkappaB by upstream kinases. However, contrary to what one would expect of a scaffold protein, our results show that RKIP has an overall inhibitory effect on the NF-kappaB transcriptional activities. Since NF-kappaB target gene expression is subject to negative regulation involving the optimal induction of negative regulators, our data support a hypothesis that RKIP inhibits NF-kappaB activity via the auto-regulatory feedback loop by rapidly inducing the expression and synthesis of inhibitors of NF-kappaB activation.
Tang
Huihui
H
Department of Biochemistry and Cancer Biology, College of Medicine, University of Toledo, Toledo, OH 43614-5804, USA.
Park
Sungdae
S
Sun
Shao-Cong
SC
Trumbly
Robert
R
Ren
Gang
G
Tsung
Eric
E
Yeung
Kam C
KC
D000818:Animals; D019556:COS Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D015151:Immunoblotting; D047468:Immunoprecipitation; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049488:Phosphatidylethanolamine Binding Protein / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects; D000099151:MAP Kinase Kinase Kinase 7
D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D053592:Interleukin-1 Receptor-Associated Kinases; D053583:Interleukin-1beta; D020930:MAP Kinase Kinase Kinases; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D049488:Phosphatidylethanolamine Binding Protein; D048029:TNF Receptor-Associated Factor 6; D000099151:MAP Kinase Kinase Kinase 7; C000606204:NFKBIA protein, human; C511482:PEBP1 protein, human