Expression of NF-kappaB in epidermis and the relationship between NF-kappaB activation and inhibition of keratinocyte growth

Takao, Joe; Yudate, Tatsuo; Das, Aditi; Shikano, Sojin; Bonkobara, Makoto; Ariizumi, Kiyoshi; Cruz, Ponciano D.

doi:10.1046/j.1365-2133.2003.05285.x

Cited by 81 publications

(72 citation statements)

References 19 publications

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“…NF-B is a crucial factor for the immunoinflammatory responses and is also implicated in various skin diseases including allergic dermatitis, psoriasis vulgaris, and skin cancer (Bell et al, 2003). Hence, although NF-B is involved in maintaining the skin homeostasis (Pasparakis et al, 2002;Takao et al, 2003), excessive activation is pathogenic. Thus, inhibition of NF-B is considered to prevent the pathogenetic changes induced by UVB.…”

Section: Discussionmentioning

confidence: 99%

Prevention of the Ultraviolet B-Mediated Skin Photoaging by a Nuclear Factor κB Inhibitor, Parthenolide

Tanaka¹,

Hasegawa²,

Asamitsu³

et al. 2005

J Pharmacol Exp Ther

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The skin photoaging is characterized by keratinocyte hyperproliferation and degradation of collagen fibers, causing skin wrinkling and laxity and melanocyte proliferation that leads to pigmentation. UV is considered to be a major cause of such skin changes. It is well established that nuclear factor B (NF-B) is activated upon UV irradiation and induces various genes including interleukin-1 (IL-1), tumor necrosis factor ␣ (TNF␣), and matrix metalloprotease-1 (MMP-1). It is also known that basic fibroblast growth factor (bFGF) production is induced by UV and promotes the proliferation of skin keratinocytes and melanocytes. We found that UVB, IL-1, and TNF␣ induced NF-B activation and then produced MMP-1 and bFGF in HaCaT keratinocytes and skin fibroblasts. In this experiment, we examined if parthenolide, an NF-B inhibitor, could block the UVB-mediated skin changes. We found that parthenolide could effectively inhibit the gene expression mediated by NF-B and the production of bFGF and MMP-1 from cells overexpressing p65, a major subunit of NF-B. We also found that parthenolide could inhibit the UVB-induced proliferation of keratinocytes and melanocytes in the mouse skin. These findings suggest that NF-B inhibitors should be useful for the prevention of skin photoaging.

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Section: Discussionmentioning

confidence: 99%

Prevention of the Ultraviolet B-Mediated Skin Photoaging by a Nuclear Factor κB Inhibitor, Parthenolide

Tanaka¹,

Hasegawa²,

Asamitsu³

et al. 2005

J Pharmacol Exp Ther

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“…The same study demonstrates that ␣6␤4 also regulates the translocation of NF-B to the nucleus and that this is important for cell cycle progression in primary keratinocytes plated on laminin-5 (62). However, there are considerable data that suggest NF-B activation inhibits keratinocyte proliferation in both murine and human skin in vivo and in vitro (78,79,90,102). In fact, the inhibition of NF-B in the presence of activated Ras can trigger tumorigenesis in the human epidermis, which is dependent on ␣6␤4 (10).…”

Section: Role Of ␣6␤4 In Biological Processesmentioning

confidence: 99%

Multiple Functions of the Integrin α6β4 in Epidermal Homeostasis and Tumorigenesis

Wilhelmsen

Litjens

Sonnenberg

2006

Molecular and Cellular Biology

126

135

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Since the discovery of the ␣6␤4 integrin in the late 1980s, our understanding of its role in providing stable adhesion of epithelial cells to basement membranes (BM) has significantly increased. ␣6␤4 plays a key role in the formation and stabilization of junctional adhesion complexes called hemidesmosomes (HDs) that are connected to the intermediate filament (IF) system, as well as in the regulation of a variety of signaling processes. However, it is not clear as yet whether ␣6␤4 participates in cell signaling by serving as a substrate for tyrosine kinases and as an adaptor for their associated signaling proteins or whether its role in cellular processes is passive, involving regulation of the assembly and disassembly of HDs. In this review, we will discuss the roles attributed to ␣6␤4 and the controversies in the field. HISTORY OF THE ␣6␤4 INTEGRINThe integrin ␣6␤4 was discovered in the late 1980s by two different groups and was called either ␣E␤4 or Ic-Ic binding protein (Ic-IcBP) (36, 85). The Ic subunit had previously been shown to form a complex with glycoprotein IIa on platelets (86), which was subsequently identified as the common ␤1 subunit of the integrin family (63). Since the Ic subunit was immunologically and biochemically different from the five integrin ␣ subunits known at that time, it was named ␣6 and the complex of ␣6 with ␤1 was called VLA-6 (30). Subsequently IcBP, which for an integrin subunit had the unusual size of approximately 200 kDa, was found to be identical to the ␤4 subunit of the ␣E␤4 complex (29). The discovery of the integrin ␣6␤4 demonstrated that a particular ␣ subunit can dimerize with more than one ␤ subunit, a property that was then thought to be unique for ␤ subunits. In further studies, the tumor antigens TSP-180 and A9 were found to be identical to ␣6␤4 (39, 93). Increased expression of ␣6␤4 and changes in its distribution were then correlated with increased aggressiveness of tumors and poor prognosis (15,97). At the same time, ␣6␤4 was also found to be a component of HDs (34,84,87). Although ␣6␤4, like ␣6␤1, can interact with different laminin isoforms, its preferred ligand in the epidermal BM is laminin-5 (4, 57, 71).Sequencing of ␤4 revealed that its large size is due to an unusually long cytoplasmic domain of over 1,000 amino acids (31,89). This domain contains two pairs of type III fibronectin (FNIII) domains, separated by a connecting segment (CS) (Fig. 1). A Na-Ca exchanger (CalX) motif precedes the first FNIII domain, but its function is still not clear (77). Importantly, ␣6␤4 was found to be associated with keratin IFs instead of with actin like other integrins (26, 84). The association with IFs is mediated by the hemidesmosomal components plectin and BP230 (27,58,70). The importance of ␤4 for adhesion to the BM became evident in ␤4 knockout mice that developed severe blistering of the skin (14, 92). This was in line with findings, just prior to these studies, that a mutation in the ␤4 gene (ITGB4) is responsible for the pyloric atresia associated with junctional ...

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“…S1A). In mice, NF-κB proteins are mainly present in basal keratinocytes (Takao et al, 2003), which are mitotically active and provide new cells that gradually undergo differentiation toward the skin surface. To better characterize the GFP signal in the skin, we took advantage of the Tg(krt19:dTomato) fish, in which basal keratinocytes are fluorescently labeled (Fischer et al, 2014).…”

Section: Design Of the Psgnluc Reportermentioning

confidence: 99%

A high-sensitivity bi-directional reporter to monitor NF-κB activity in cell culture and zebrafish in real time

Kuri

Ellwanger

Kufer

et al. 2017

Journal of Cell Science

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Nuclear factor (NF)-κB transcription factors play major roles in numerous biological processes including development and immunity. Here, we engineered a novel bi-directional NF-κB-responsive reporter, pSGNluc, in which a high-affinity NF-κB promoter fragment simultaneously drives expression of luciferase and GFP. Treatment with TNFα (also known as TNF) induced a strong, dosedependent luciferase signal in cell culture. The degree of induction over background was comparable to that of other NF-κB-driven luciferase reporters, but the absolute level of expression was at least 20-fold higher. This extends the sensitivity range of otherwise difficult assays mediated exclusively by endogenously expressed receptors, as we show for Nod1 signaling in HEK293 cells. To measure NF-κB activity in the living organism, we established a transgenic zebrafish line carrying the pSGNluc construct. Live in toto imaging of transgenic embryos revealed the activation patterns of NF-κB signaling during embryonic development and as responses to inflammatory stimuli. Taken together, by integrating qualitative and quantitative NF-κB reporter activity, pSGNluc is a valuable tool for studying NF-κB signaling at high spatiotemporal resolution in cultured cells and living animals that goes beyond the possibilities provided by currently available reporters.

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Expression of NF-kappaB in epidermis and the relationship between NF-kappaB activation and inhibition of keratinocyte growth

Abstract: NF-kappaB is constitutively expressed in a resting state in both human cultured keratinocytes and the epidermis. Activation of NF-kappaB is required for PMA-induced keratinocyte growth arrest.

Cited by 81 publications

References 19 publications

Prevention of the Ultraviolet B-Mediated Skin Photoaging by a Nuclear Factor κB Inhibitor, Parthenolide

Prevention of the Ultraviolet B-Mediated Skin Photoaging by a Nuclear Factor κB Inhibitor, Parthenolide

Multiple Functions of the Integrin α6β4 in Epidermal Homeostasis and Tumorigenesis

A high-sensitivity bi-directional reporter to monitor NF-κB activity in cell culture and zebrafish in real time

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