Regulation of NF κB by NSD1/FBXL11-dependent reversible lysine methylation of p65

Lü, Tao; Jackson, Mark W.; Wang, Benlian; Yang, Maojing; Chance, Mark R.; Miyagi, Masaru; Gudkov, Andrei V.; Stark, George R.

doi:10.1016/j.cyto.2009.07.079

Cited by 60 publications

(81 citation statements)

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“…3B). In addition, we identified a missense mutation (c.T3380G of NM_02245 encoding p.Leu1127Arg) in NSD1 (nuclear receptor binding SET domain protein 1), reduced expression of which is known to decrease NF-κB activation (23). Again, the knockdown of NSD1 increased DOX resistance consistent with reduced NF-κB activation, in turn, leading to reduced apoptosis (Fig.…”

Section: Transcriptome Sequencing and Pathway Analysis For Resistancementioning

confidence: 72%

Rapid emergence and mechanisms of resistance by U87 glioblastoma cells to doxorubicin in an in vitro tumor microfluidic ecology

Han

Jun

Kim

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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In vitro prediction of the probable rapid emergence of resistance to a drug in tumors could act to winnow out potential candidates for further costly development. We have developed a microfluidic device consisting of ∼500 hexagonal microcompartments that provides a complex ecology with wide ranges of drug and nutrient gradients and local populations. This ecology of a fragmented metapopulation induced the drug resistance in stage IV U87 glioblastoma cells to doxorubicin in 7 d. Exome and transcriptome sequencing of the resistant cells identified mutations and differentially expressed genes. Gene ontology and pathway analyses of the genes identified showed that they were functionally relevant to the established mechanisms of doxorubicin action. Specifically, we identified (i) a frame-shift insertion in the filamin-A gene, which regulates the influx and efflux of topoisomerase II poisons; (ii) the overexpression of aldo-keto reductase enzymes, which convert doxorubicin into doxorubicinol; and (iii) activation of NF-κB via alterations in the nucleotide-binding oligomerization domain (NOD)-like receptor signaling pathway from mutations in three genes (CARD6, NSD1, and NLRP13) and the overexpression of inflammatory cytokines. Functional experiments support the in silico analyses and, together, demonstrate the effects of these genetic changes. Our findings suggest that, given the rapid evolution of resistance and the focused response, this technology could act as a rapid screening modality for genetic aberrations leading to resistance to chemotherapy as well as counter selection of drugs unlikely to be successful ultimately.

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Section: Transcriptome Sequencing and Pathway Analysis For Resistancementioning

confidence: 72%

Rapid emergence and mechanisms of resistance by U87 glioblastoma cells to doxorubicin in an in vitro tumor microfluidic ecology

Han

Jun

Kim

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Both NSD1 and NSD2 regulate methylation of lysine 36 on histone 3, a process which is crucial to chromatin regulation. In addition, both NSD1 and NSD2 have been shown to regulate methylation of lysine 20 on histone 4 and the non-histone p65 subunit of nuclear factor-jB (NFjB) (Berdasco et al 2009;Lu et al 2010;Rayasam et al 2003;Wang et al 2007;Pei et al 2011). Aberrant expressions of NSD1 and NSD2 are associated with multiple types of cancer, including acute myeloid leukemia, multiple myeloma, and lung cancer (Jaju et al 2001;Keats et al 2003;La Starza et al 2004;Tonon et al 2005;Wang et al 2007).…”

Section: Biological Contextmentioning

confidence: 97%

NMR backbone resonance assignment and solution secondary structure determination of human NSD1 and NSD2

et al. 2016

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Proteins of the NSD family are histone-methyl transferases with critical functions in the regulation of chromatin structure and function. NSD1 and NSD2 are homologous proteins that function as epigenetic regulators of transcription through their abilities to catalyse histone methylation. Misregulation of NSD1 and NSD2 expression or mutations in their genes are linked to a number of human diseases such as Sotos syndrome, and cancers including acute myeloid leukemia, multiple myeloma, and lung cancer. The catalytic domain of both proteins contains a conserved SET domain which is involved in histone methylation. Here we report the backbone resonance assignments and secondary structure information of the catalytic domains of human NSD1 and NSD2.

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“…KDM2A is able to demethylate histone H3K36me1/2 and non-histone proteins, like RelA (p65), a subunit of nuclear factor-κB (NF-κB) (Lu et al, 2010). Although all the three methylated states of H3K36 can insert into the catalytic pocket of KDM2A, steric hindrance to the rotation of 2-OG prevents it changing from the ''off-line'' to ''in-line'' modes in the presence of H3K36me3 .…”

Section: Kdm2 Subfamilymentioning

confidence: 99%

Epigenetic targets and drug discovery Part 2: Histone demethylation and DNA methylation

Liu

Lau

et al. 2015

Pharmacology & Therapeutics

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Regulation of NF κB by NSD1/FBXL11-dependent reversible lysine methylation of p65

Cited by 60 publications

References 0 publications

Rapid emergence and mechanisms of resistance by U87 glioblastoma cells to doxorubicin in an in vitro tumor microfluidic ecology

Rapid emergence and mechanisms of resistance by U87 glioblastoma cells to doxorubicin in an in vitro tumor microfluidic ecology

NMR backbone resonance assignment and solution secondary structure determination of human NSD1 and NSD2

Epigenetic targets and drug discovery Part 2: Histone demethylation and DNA methylation

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