Transcriptional regulatory effects of lymphoma-associated NFKB2/lyt10 protooncogenes

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

doi:10.1038/sj.onc.1203432

Cited by 23 publications

(22 citation statements)

References 77 publications

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“…In contrast to Hut-78, overexpressed p52 only transiently induced TRAF1 expression in lymphocytes and rather appeared to act as homodimers harbouring repressing transcriptional activities in vitro and in vivo (Wang et al, 2008). Those data are in agreement with earlier studies showing that Hut-78 harboured an enhanced transactivation potential compared to p52 (Chang et al, 1995;Epinat et al, 2000;Kim et al, 2000). Thus, overproduced p52 in lymphocytes triggers the expression of many common target genes, among which is MMP9, yet several genes such as TRAF1 required to drive lymphomagenesis in vivo are specifically induced by Hut-78 but not by p52.…”

Section: Discussionsupporting

confidence: 90%

Matrix Metalloproteinase-9 gene induction by a truncated oncogenic NF-κB2 protein involves the recruitment of MLL1 and MLL2 H3K4 histone methyltransferase complexes

et al. 2009

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Constitutive nuclear factor (NF)-jB activation in haematological malignancies is caused in several cases by loss of function mutations within the coding sequence of NF-jB inhibitory molecules such as IjBa or p100. Hut-78, a truncated form of p100, constitutively generates p52 and contributes to the development of T-cell lymphomas but the molecular mechanism underlying this oncogenic potential remains unclear. We show here that MMP9 gene expression is induced through the alternative NF-jB-activating pathway in fibroblasts and also on Hut-78 or p52 overexpression in fibroblasts as well as in lymphoma cells. p52 is critical for Hut-78-mediated MMP9 gene induction as a Hut-78 mutant as well as other truncated NF-jB2 proteins that are not processed into p52 failed to induce the expression of this metalloproteinase. Conversely, MMP9 gene expression is impaired in p52-depleted HUT-78 cells. Interestingly, MLL1 and MLL2 H3K4 methyltransferase complexes are tethered by p52 on the MMP9 but not on the IjBa promoter, and the H3K4 trimethyltransferase activity recruited on the MMP9 promoter is impaired in p52-depleted HUT-78 cells. Moreover, MLL1 and MLL2 are associated with Hut-78 in a native chromatin-enriched extract. Thus, we identified a molecular mechanism by which the recruitment of a H3K4 histone methyltransferase complex on the promoter of a NF-jB-dependent gene induces its expression and potentially the invasive potential of lymphoma cells harbouring constitutive activity of the alternative NF-jB-activating pathway.

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Section: Discussionsupporting

confidence: 90%

Matrix Metalloproteinase-9 gene induction by a truncated oncogenic NF-κB2 protein involves the recruitment of MLL1 and MLL2 H3K4 histone methyltransferase complexes

et al. 2009

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“…For example, the C terminally truncated p100 proteins from tumor cells are generally nuclear proteins when overexpressed in tissue culture cells (Migliazza et al, 1994;Zhang et al, 1994); homodimers or heterodimers containing the truncated p100 proteins can bind to DNA (Thakur et al, 1994;Zhang et al, 1994;Chang et al, 1995;Derudder et al, 2003), and the tumor-specific p100 proteins have an increased ability to activate transcription in kB-site reporter gene assays (Chang et al, 1995;Epinat et al, 2000;Kim et al, 2000). Because the deletions in NFKB2 invariably result in the removal of residues important for the regulated processing of p100 to p52 (Xiao et al, 2001), the C-terminal truncations sometimes result in increased production of p52-containing dimers (Thakur et al, 1994;Derudder et al, 2003).…”

Section: Multiple Familial Trichoepitheliomamentioning

confidence: 99%

Mutations in the NF-κB signaling pathway: implications for human disease

2006

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“…As discussed above, a variety of rearrangements or deletions in the nfkb2 locus have been identified in human lymphoid malignancies unrelated to HTLV-I infection. Mutations cluster within the 3 0 ankyrin-encoding domain of the nfkb2 gene and lead to production of abnormal proteins, which results in loss of IkB function (Kim et al, 2000) and constitutive p52 production and DNA-binding activity (reviewed in Neri et al, 1996). Deregulated production of p52 has also been reported in breast cancer cells, CTCL-derived cell lines and Hodgkin Reed-Sternberg cells (Thakur et al, 1994;Cogswell et al, 2000;Nonaka et al, 2005) These cancer cells may require an activity that induces the processing of p100 and disrupts its potent IkB function to keep the high NF-kB activity.…”

Section: Mechanism Of Tax-independent Nf-jb Activationmentioning

confidence: 99%