Transcriptional regulatory effects of lymphoma-associated NFKB2/lyt10 protooncogenes.
C-terminal truncations of the NFKB2 p100 gene product have been observed in a number of cases of human cutaneous T cell lymphomas, as well as human B-cell lymphomas and myelomas. The contribution of these alterations to lymphomagenesis is not understood; however, truncation at amino acid 666 to generate 80 - 85 kD proteins in the HUT78 cell line is associated with addition of a short (serine-alanine-serine) fusion at the 3' end of p80HT, as well as with increased expression of NFKB2 mRNA. We therefore examined the effects of p80HT on the regulation of NFKB2 expression, as well as the properties of a series of other tumor-associated, and site directed mutations of NFKB2. While p80HT had not itself acquired novel transcriptional activation properties with respect to the NFKB2 P1 or P2 promoters or the IL-6 kappaB promoter, p80HT had lost the potent inhibitory (IkappaB-like) activity associated with the wild-type, p100 gene product. Loss of the inhibitory property depended on the SAS residues in the fusion protein, direct truncation at aa666 was fully inhibitory, as was a substitution of three alanines for the SAS residues. The presence of as few as two C-terminal ankyrin motifs was sufficient for inhibition of NF-kappaB-mediated transcriptional activation. Assays of a series of additional lymphoma-associated NF-kappaB-2 truncation suggested that the C-terminal truncation associated with these proteins was also associated with a loss of the IkappaB-like activities of p100 NF-kappaB-2, for at least some NF-kappaB target promoters. Thus, the loss of IkappaB-like activity of lymphoma-associated NFKB2 mutations may play an important role in the genesis of a subset of human lymphomas.
Kim
K E
KE
Center for Advanced Biotechnology and Medicine, University of Medicine and Dentistry - Robert Wood Johnson Medical School, Piscataway, New Jersey, NJ 08854, USA.
Gu
C
C
Thakur
S
S
Vieira
E
E
Lin
J C
JC
Rabson
A B
AB
D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008223:Lymphoma / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics*; D052003:NF-kappa B p52 Subunit; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011519:Proto-Oncogenes; D014158:Transcription, Genetic
D015850:Interleukin-6; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; C036987:protein p80