Overexpression of I kappa B alpha without inhibition of NF-kappaB activity and mutations in the I kappa B alpha gene in Reed-Sternberg cells.
The transcription factor NF kappa B (NF-kappaB) mediates the expression of numerous genes involved in diverse functions such as inflammation, immune response, apoptosis, and cell proliferation. We recently identified constitutive activation of NF-kappaB (p50/p65) as a common feature of Hodgkin/Reed-Sternberg (HRS) cells preventing these cells from undergoing apoptosis and triggering proliferation. To examine possible alterations in the NF-kappaB/IkappaB system, which might be responsible for constitutive NF-kappaB activity, we have analyzed the inhibitor I kappa B alpha (IkappaBalpha) in primary and cultured HRS cells on protein, mRNA, and genomic levels. In lymph node biopsy samples from Hodgkin's disease patients, IkappaBalpha mRNA proved to be strongly overexpressed in the HRS cells. In 2 cell lines (L428 and KM-H2), we detected mutations in the IkappaBalpha gene, resulting in C-terminally truncated proteins, which are presumably not able to inhibit NF-kappaB-DNA binding activity. Furthermore, an analysis of the IkappaBalpha gene in single HRS cells micromanipulated from frozen tissue sections showed a monoallelic mutation in 1 of 10 patients coding for a comparable C-terminally truncated IkappaBalpha protein. We suggest that the observed IkappaBalpha mutations contribute to constitutive NF-kappaB activity in cultured and primary HRS cells and are therefore involved in the pathogenesis of these Hodgkin's disease (HD) patients. The demonstrated constitutive overexpression of IkappaBalpha in HRS cells evidences a deregulation of the NF-kappaB/IkappaB system also in the remaining cases, probably due to defects in other members of the IkappaB family.
Emmerich
F
F
Humboldt University of Berlin, Universitätsklinikum Charité, Robert-Rössle-Klinik, Berlin, Germany.
Meiser
M
M
Hummel
M
M
Demel
G
G
Foss
H D
HD
Jundt
F
F
Mathas
S
S
Krappmann
D
D
Scheidereit
C
C
Stein
H
H
Dörken
B
B
D001483:Base Sequence; D015972:Gene Expression Regulation, Neoplastic; D006689:Hodgkin Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D016539:Reed-Sternberg Cells / Q000378:metabolism*; D016415:Sequence Alignment
D016328:NF-kappa B; D012333:RNA, Messenger