title: ABINs inhibit EGF receptor-mediated NF-kappaB activation and growth of EGF receptor-overexpressing tumour cells.
abstract: The epidermal growth factor receptor (EGFR) is frequently overexpressed in various tumours of epidermal origin and is held responsible for tumourigenicity and tumour persistence. Increased nuclear factor (NF)-kappaB activity has been suggested to be involved in the malignant behaviour of EGFR-overexpressing cells. However, the mechanisms that regulate EGF-induced NF-kappaB activation are still largely unknown. Here we show that EGF can induce NF-kappaB-dependent gene expression independently from IkappaBalpha degradation or p100 processing in EGFR-overexpressing HEK293T cells. Moreover, EGF-induced NF-kappaB activation could be inhibited by overexpression of ABINs, which were previously identified as intracellular inhibitors of tumour necrosis factor, interleukin-1 and lipopolysaccharide-induced NF-kappaB activation. Knockdown of ABIN-1 by RNA interference boosted the NF-kappaB response upon EGF stimulation. The C-terminal ubiquitin-binding domain containing region of ABINs was crucial and sufficient for NF-kappaB inhibition. Adenoviral gene transfer of ABINs reduced constitutive NF-kappaB activity as well as the proliferation of EGFR-overexpressing A431 and DU145 human carcinoma cells. Altogether, these results demonstrate an important role for an ABIN-sensitive non-classical NF-kappaB signalling pathway in the proliferation of EGFR-overexpressing tumour cells, and indicate a potential use for ABIN gene therapy in the treatment of cancer.
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Huang
authors.forename: L
authors.initials: L
authors.lastname: Verstrepen
authors.forename: K
authors.initials: K
authors.lastname: Heyninck
authors.forename: A
authors.initials: A
authors.lastname: Wullaert
authors.forename: H
authors.initials: H
authors.lastname: Revets
authors.forename: P
authors.initials: P
authors.lastname: De Baetselier
authors.forename: R
authors.initials: R
authors.lastname: Beyaert
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000502:physiology; D015316:Genetic Therapy; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D052003:NF-kappa B p52 Subunit / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; C000606204:NFKBIA protein, human; C117046:TNIP1 protein, human; C434062:TNIP2 protein, human; D019938:Cyclin D1; D000072000:NF-KappaB Inhibitor alpha; D004815:Epidermal Growth Factor; D066246:ErbB Receptors