Transcriptional regulatory effects of lymphoma-associated NFKB2/lyt10 protooncogenes

Kyoung Eun Kim, Chunyan Gu, Sanjay Thakur, Eric Vieira, Jennifer C. Lin, Arnold B. Rabson

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

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 κB promoter, p80HT had lost the potent inhibitory (IκB-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-κB-mediated transcriptional activation. Assays of a series of additional lymphoma-associated NF-κB-2 truncation suggested that the C-terminaI truncation associated with these proteins was also associated with a loss of the IκB-like activities of p100 NF-κB-2, for at least some NF-κB target promoters. Thus, the loss of IκB-like activity of lymphoma-associated NFKB2 mutations may play an important role in the genesis of a subset of human lymphomas.

Original languageEnglish (US)
Pages (from-to)1334-1345
Number of pages12
JournalOncogene
Volume19
Issue number10
DOIs
StatePublished - Mar 2 2000

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Keywords

  • Iymphoma transcription
  • NF-κB
  • NF-κB-2
  • Protooncogene

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