Transcription factor NF-kappaB is constitutively activated in acute lymphoblastic leukemia cells.
The pleiotropic transcription factor NF-kappaB controls cellular apoptotic and growth processes and increasing evidence suggests a role in tumorigenesis. We describe here that constitutively activated NF-kappaB complexes are found in the vast majority (39 out of 42 samples) of childhood acute lymphoblastic leukemia (ALL) without any subtype restriction. Electrophoretic shift analysis further demonstrates that these complexes are composed of p50-p50 and p65-p50 dimers. Proteasome inhibition in primary ALL cultures results in a hyperphosphorylated form of IkappaBalpha, indicating that activation of upstream kinases, which trigger IkappaBalpha degradation, has led to nuclear translocation of NF-kappaB. Careful inhibition of cellular proteolytic activities is of importance when analyzing extracts from primary ALL cells. Degradation of p65 and other proteins in ALL samples could be specifically suppressed by alpha-1 antitrypsin. Constitutive NF-kappaB activation is thus a common characteristic of childhood ALL and strongly suggests a critical role of this factor for leukemia cell survival.
Kordes
U
U
Max-Delbrück-Centrum for Molecular Medicine, Universitätsklinikum Charité, Campus Berlin-Buch, Germany.
Krappmann
D
D
Heissmeyer
V
V
Ludwig
W D
WD
Scheidereit
C
C
D002648:Child; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D019281:Dimerization; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D020672:I-kappa B Proteins; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000378:metabolism; D046911:Macromolecular Substances; D008970:Molecular Weight; D009097:Multienzyme Complexes / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000737:chemistry / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D046911:Macromolecular Substances; D009097:Multienzyme Complexes; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009363:Neoplasm Proteins; D000072000:NF-KappaB Inhibitor alpha; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex