Association between activation of atypical NF-kappaB1 p105 signaling pathway and nuclear beta-catenin accumulation in colorectal carcinoma.
Recent studies have demonstrated that increased expression of coding region determinant-binding protein (CRD-BP) in response to beta-catenin signaling leads to the stabilization of beta-TrCP1, a substrate-specific component of SCF E3 ubiquitin ligase complex, resulting in an accelerated degradation of IkappaBalpha and activation of canonical nuclear factor-kappaB (NF-kappaB) pathway. Here, we show that the noncanonical NF-kappaB1 p105 pathway is constitutively activated in colorectal carcinoma specimens, being particularly associated with beta-catenin-mediated increased expression of CRD-BP and beta-TrCP1. In the carcinoma tissues exhibiting high levels of nuclear beta-catenin the phospho-p105 levels were increased and total p105 amounts were decreased in comparison to that of normal tissue indicating an activation of this NF-kappaB pathway. Knockdown of CRD-BP in colorectal cancer cell line SW620 resulted in significantly higher basal levels of both NF-kappaB inhibitory proteins, p105 and IkappaBalpha. Furthermore decreased NF-kappaB binding activity was observed in CRD-BP siRNA-transfected SW620 cells as compared with those transfected with control siRNA. Altogether, our findings suggest that activation of NF-kappaB1 p105 signaling in colorectal carcinoma might be attributed to beta-catenin-mediated induction of CRD-BP and beta-TrCP1.
Lauscher
Johannes C
JC
Department of Surgery I, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
Gröne
Jörn
J
Dullat
Sonja
S
Hotz
Birgit
B
Ritz
Jörg-P
JP
Steinhoff
Ulrich
U
Buhr
Heinz-J
HJ
Visekruna
Alexander
A
D001483:Base Sequence; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism*
D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D034741:RNA, Small Interfering; D051176:beta Catenin