Disease relevance of NFKB2

• Here we examine the biochemical basis for the transcriptional regulation of HIV by NFKB2 [1].
• In particular, the NFKB2 gene, localized on chromosome 10q24, represents a candidate proto-oncogene, since it has been found rearranged in certain types of lymphoma and more commonly in cutaneous lymphoma [2].
• The NFKB-2 gene is a candidate proto-oncogene since it is involved in lymphoma-associated chromosomal aberrations [3].
• In one case of multiple myeloma (MM), cloning and sequencing analysis of reciprocal breakpoint sites showed that they occurred within intron 15 of the NFKB2 gene and led to the complete deletion of the 3' portion of the gene coding for the ankyrin domain [4].
• Furthermore, the NFKB2 precursor is physically associated with c-Rel and with Tax in HTLV-I infected cells [5].

High impact information on NFKB2

• B cell lymphoma-associated chromosomal translocation involves candidate oncogene lyt-10, homologous to NF-kappa B p50 [6].
• One, named MBP-2 (major histocompatibility complex-binding protein 2), encodes a factor that has DNA-binding properties similar, if not identical, to the H2TF1 transcription factor [7].
• H2TF1 is a constitutive ubiquitous transcription factor that activates expression of major histocompatibility complex class I genes [7].
• In particular, we detected rearrangements of the bcl-1 locus (2 cases), the bcl-2 gene (2 cases), the NFKB2/lyt-10 gene (2 cases), and the bcl-6 gene (1 case); interestingly, 4 of these cases showed a germline arrangement of the Ig genes [8].
• Moreover, our results suggest that tal-1 gene deletions may play a pathogenetic role in non-acute T-cell malignancies and that, in the context of lymphoid malignancies, CLs may represent a favorable target for the possible oncogenic potential of the NFKB2/lyt-10 gene [8].

Biological context of NFKB2

• These data suggest that binding of the NFKB2 subunit to the HIV enhancer is facilitated by RelA(p65) and that this NFKB2(p49)/p65 heterodimeric complex mediates transcriptional activation which is subject to regulation by MAD-3 [1].
• Structural and functional characterization of the promoter regions of the NFKB2 gene [9].
• Based on the nucleotide sequence of cDNA clones and the 5' flanking genomic region of the NFKB2 gene, RT-PCR analysis in a number of human cell lines demonstrated the presence of two alternative noncoding first exons (1a and 1b) [9].
• The involvement of the candidate proto-oncogene NFKB2/lyt-10 in lymphoid malignancies [2].
• Rearrangements cluster within the carboxy-terminal ankyrin domain of the NFKB2 gene leading to the production of carboxy-terminally truncated proteins which, in some cases, are fused to heterologous protein domains [2].

Anatomical context of NFKB2

• In one case of T-cell cutaneous lymphoma (CTCL) and in one of B-cell chronic lymphocytic leukemia (B-CLL), NFKB2 rearrangements occurred, respectively, within exons 18 and 20 of the gene and involved recombinations with distinct regions of chromosome 10q24 [4].
• The NFKB2 gene represents a candidate proto-oncogene, since it has been found to be involved in a chromosomal translocation t(10;14)(q24;q32) in one case of B-cell lymphoma and in gene rearrangements in various types of lymphoid malignancies [4].
• Regulation of p100 (NFKB2) expression in human monocytes in response to inflammatory mediators and lymphokines [10].
• NFKB2 is ubiquitously expressed, highest in lymph nodes and thymus, underlining its role in the immune function [11].
• The expression of both normal and mutant NFKB-2 proteins has a lethal effect on lymphoblastoid cells and a cytotoxic effect was also observed in murine fibroblasts [12].

Physical interactions of NFKB2

• We show here that NF-kappa B p100 is a component of the previously identified DNA-binding activity H2TF1 [13].

Other interactions of NFKB2

• NF-kappa B p100 (Lyt-10) is a component of H2TF1 and can function as an I kappa B-like molecule [13].
• In both of these cases, the rearrangements led to specific carboxy-terminal truncations of NFKB2 generating abnormal transcripts that coded for proteins lacking portions of the ankyrin domain [4].
• Direct measurement of mRNAs showed increased gene expression of both types of transcription factors in chondroinduced hDFs, including NFKB2 (290% of control), RELA (160%), and GATA2 (190%) [14].
• Germline configuration of nfkb2, c-rel and bcl3 in childhood acute lymphoblastic leukemia (ALL) [15].
• We focused on examining genes found to be up-regulated according to the microarray analysis and selected three putative target genes, NFKB2, SMARCD3, and NR4A3, for further investigation [16].

Analytical, diagnostic and therapeutic context of NFKB2

• Fluorescent in situ hybridization (FISH) analysis showed that the novel regions involved in the NFKB2 rearrangement originated from chromosome 7q34, thus implying the occurrence of a t(7;10)(q34;q24) reciprocal chromosomal translocation [4].
• The rearrangement has truncated NFKB2 sequences within the 3' ankyrin domain, leading to the production of truncated mRNA species and proteins as detected by Northern blot and immunoprecipitation analysis, respectively [17].
• Electrophoretic mobility shift assays performed on HUT78 nuclear extracts indicate that the abnormal NFKB2 proteins bind kappa B sites specifically and alter the composition of NF-kappa B complexes in HUT78 cells [17].
• By fluorescence in situ hybridization, mouse NFKB2 was mapped to Chromosome (Chr) MMU 19C3-D2, which is homologous to human Chr 10q24, at which position the human NFKB2 was previously located [11].
• H2TF1 was purified by a novel affinity chromatography method and identified as the NF-kappa B2 p100 polypeptide by peptide sequencing as well as by reactivity with a specific antiserum [18].

References