The inducible transcription factor NF-<i>κ</i>B: structure-function relationship of its protein subunits

Grimm, Silke; Baeuerle, Patrick A.

doi:10.1042/bj2900297

Cited by 411 publications

(247 citation statements)

References 83 publications

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“…Their activity is regulated by specific inhibitor proteins, the inhibitory protein Bs (I Bs) 4 that retain the transcription factor in a latent stage in the cytoplasm (21,22). A broad range of stimuli leads to their phosphorylation by I B kinase complexes that contain the related IKK␣ and IKK␤ kinases as well as additional proteins (21,23,24).…”

Section: N Atural Killer Cells Survey Emerging Tumors and Can Clearmentioning

confidence: 99%

“…3D). Results so far indicated that IL-2 stimulation of NK3.3 cells leads to a PDTC and TPCK sensitive activation of the NF-B signaling pathway, including IKK␣ activation, I B␣ degradation, and the formation of heterodimeric p50/p65 complexes, i.e., transcriptionally active NF-B molecules (21)(22)(23).…”

Section: Activation Of the Nf-b Signaling Pathway By Il-2 In Nk33 Cellsmentioning

confidence: 99%

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A Role for NF-κB Activation in Perforin Expression of NK Cells Upon IL-2 Receptor Signaling

Zhou

Zhang

Lichtenheld

et al. 2002

The Journal of Immunology

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Optimal NK cell development and activation as well as cytolytic activity involves IL-2Rβ signals that also up-regulate expression of the pore-forming effector molecule perforin. Although the Jak/Stat pathway and specifically Stat5 transcription factors are required to promote many of the respective downstream events, the role of additional signaling pathways and transcription factors remains to be clarified. This report investigates the role of NF-κB activation for perforin expression by NK cells. It is demonstrated that IL-2-induced up-regulation of perforin in primary NK cells and in a model cell line is blocked by two pharmacological agents known to inhibit NF-κB activation. Direct evidence for the activation of the NF-κB pathway by IL-2R signals in NK cells involves activation of the IKKα kinase, inhibitory protein κBα degradation, nuclear translocation of p50/p65 complexes, and ultimately, transcriptional activation of the perforin gene via an NF-κB binding element in its upstream enhancer. Taken together, these observations strongly suggest that IL-2R signals can activate a pathway leading to NF-κB activation in NK cells and that this pathway is involved in the control of perforin expression.

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Section: N Atural Killer Cells Survey Emerging Tumors and Can Clearmentioning

confidence: 99%

Section: Activation Of the Nf-b Signaling Pathway By Il-2 In Nk33 Cellsmentioning

confidence: 99%

A Role for NF-κB Activation in Perforin Expression of NK Cells Upon IL-2 Receptor Signaling

Zhou

Zhang

Lichtenheld

et al. 2002

The Journal of Immunology

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“…This ubiquitous transcription factor, whose expression is altered in some cancer cells ( Van't Veer et al, 1993;Bours et al, 1994;Mukhopadhyay et al, 1995), is known to control the expression of numerous genes including genes coding for proteins that are important for cell adhesion (Voraberger et al, 1991;Whelan et al, 1991;Iademarco et al, 1992). NF-kB was originally described as being present in the cytosol of many cell types as an inactive heterodimer composed of 50 kDa (p50, NF-kB1) and 65-kDa (p65, Rel A) subunits and bound to IkB-a, one of the inhibitor proteins of the IkB family (Grilli et al, 1993;Grimm and Baeuerle, 1993;Siebenlist et al, 1994). Cloning of the cDNAs encoding NF-kB p50 and p65 subunits revealed that both proteins are homologous to the product of the c-rel proto-oncogene.…”

Section: Introductionmentioning

confidence: 99%

“…Whereas p65 is synthesized as a mature protein, p50 is derived from the amino-terminal portion of a precursor protein, p105. In the nucleus, the p50 subunit serves DNA binding while the p65 subunit has strong transactivating activity (Grimm and Baeuerle, 1993;Ballard et al, 1992). In the recent years, intense research has centered on elucidating the signaling events responsible for the dissociation of IkB-a from NF-kB, a process which is a critical limiting step in the activation of NF-kB induced by various agonists or stimuli.…”

Section: Introductionmentioning

confidence: 99%

Down-regulation of NF-κB activity and NF-κB p65 subunit expression by ras and polyoma middle T oncogenes in human colonic Caco-2 cells

et al. 1997

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The products of ras and src proto-oncogenes are frequently activated in a constitutive state in human colorectal cancer. In this study we attempted to establish whether the tumorigenic progression induced by oncogenic activation of p21 ras or pp60 c-src in human colonic cells is associated with alterations of the activity and expression of nuclear factor kB (NF-kB), a transcription factor suspected to participate in the development of cancer. To this end, we used Caco-2 cells made highly tumorigenic by transfection with an activated Val-12 human Ha-ras gene or with the polyoma middle T (PyMT) oncogene, a constitutive activator of pp60 c-src tyrosine kinase activity. Compared with control vectortransfected Caco-2 cells, both oncogene-transfected cell lines exhibited: (i) decreased constitutive NF-kB DNAbinding activity and NF-kB-mediated reporter gene expression, without alteration of their response to TNF-a for activation of these parameters; (ii) reduced NF-kB cytosolic stores along with a decreased p65 expression due, at least in part, to destabilization of p65 mRNA; (iii) a decrease in adhesion to extracellular matrix component-coated substrata which was partially corrected when stimulating NF-kB transcriptional activity with TNF-a. These results indicate that the tumorigenic progression induced by oncogenic p21 ras or PyMT/pp60 c-src in human colonic Caco-2 cells is associated with a down-regulation of p65 expression and NF-kB activity which could be responsible for the reduced adhesive properties of these cells after oncogene transfection.

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“…This phenomenon of intramolecular inhibition is supported by a growing body of evidence suggesting that the functional characteristics of an isolated transcription factor domain can be different when compared with those of the intact protein. For example, deletions or mutations outside the DNA-binding domains of p53, NFKB, and TATA-Binding Protein (TBP) substantially alter the affinity of these regulatory proteins for DNA (Lieberman et al, 1991;Hupp et al, 1992;Grimm & Baeuerle, 1993). In addition, trimerization of human and Drosophila heat shock transcription factors, HSF, is suppressed by intramolecular coiled-coil interactions (Rabindran et al, 1993).…”

mentioning

confidence: 99%

Structural coupling of the inhibitory regions flanking the ETS domain of murine Ets‐1

et al. 1996

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Several members of the ets gene family of transcription factors show negative regulation of DNA binding by intramolecular interactions. A structural mechanism for this auto-inhibition is investigated using a 161-residue N-terminal deletion mutant of murine Ets-1, Ets-1AN280. This protein shows a similar reduced affinity for DNA as native Ets-1 because it contains the ETS domain in context of the flanking amino-and carboxy-terminal regions that together mediate repression of DNA binding. The secondary structure of Ets-IAN280 was determined using NMR chemical shift, NOE, J coupling, and amide hydrogen exchange information. In addition to the winged helix-turn-helix ETS domain, Ets-1AN280 contains two a-helices in the amino-terminal inhibitory region and one a-helix in the carboxy-terminal inhibitory region. Chemical shift comparisons were made between this protein and an activated form of Ets-1 lacking the amino-terminal inhibitory region. The spectral differences demonstrate that the amino-and carboxy-terminal inhibitory sequences are structurally coupled to one another, thus explaining the observation that both regions are required for the repression of DNA binding. Furthermore, these data show that the inhibitory sequences also interact directly with the first helix of the intervening ETS domain, thereby providing a pathway for the repression of DNA binding. These results lead to a model of an inhibitory module in Ets-1 composed of both the amino-and carboxy-terminal regions interfaced with the ETS domain. This establishes the structural framework for understanding the intramolecular inhibition of Ets-1 DNA binding.Keywords: allosteric; DNA binding; ETS domain; Ets-1 and Ets-2; intramolecular inhibition; NMR; protein structure; winged helix-turn-helix DNA binding, activation, and oligomerization associated with a particular transcription factor may be governed by its subcellular localization, posttranslational modifications, ligand binding, and protein-protein interactions.Recently, data have Abbreviations: ets, E26 transformation specific; Ets-1AC428, the carboxy-terminal deletion fragment of murine Ets-1 consisting of residues 1-428; Ets-1AN280, the amino-terminal deletion fragment of murine Ets-1 consisting of residues 280-440; Ets-1AN331, the aminoterminal deletion fragment of murine Ets-1 consisting of residues 33 1-440; FID, free induction decay; HSQC, heteronuclear single quantum correlation; NOESY, nuclear Overhauser effect spectroscopy; TOCSY, total correlation spectroscopy; IPTG, isopropyl-8-D-thiogalactopyranoside; DTT, dithiothreitol; pH*, the observed pH meter reading without correction for isotope effects; wHTH, winged helix-turn-helix; HSF, heat shock transcription factors; DSS, 2,2-dimethyl-2-silapentane-5-sulfonate, sodium salt.

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The inducible transcription factor NF-κB: structure-function relationship of its protein subunits

Cited by 411 publications

References 83 publications

A Role for NF-κB Activation in Perforin Expression of NK Cells Upon IL-2 Receptor Signaling

A Role for NF-κB Activation in Perforin Expression of NK Cells Upon IL-2 Receptor Signaling

Down-regulation of NF-κB activity and NF-κB p65 subunit expression by ras and polyoma middle T oncogenes in human colonic Caco-2 cells

Structural coupling of the inhibitory regions flanking the ETS domain of murine Ets‐1

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