Bricks and mortar of the epidermal barrier

Nemes, Zoltán; Steinert, Peter M.

doi:10.1038/emm.1999.2

Cited by 502 publications

(422 citation statements)

References 177 publications

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“…to produce the suprabasal epidermal layers (Nemes and Steinert, 1999). The epidermis provides protection against cancer-promoting agents present in the environment.…”

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confidence: 99%

Keratinocyte proliferation, differentiation, and apoptosis—Differential mechanisms of regulation by curcumin, EGCG and apigenin

Balasubramanian

Eckert

2007

Toxicology and Applied Pharmacology

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We have proposed that it is important to examine the impact of chemopreventive agents on the function of normal human epidermal keratinocytes, since these cells comprise the barrier that protects the body from a range of environmental insults. In this context, it is widely appreciated that cancer may be retarded by consumption or topical application of naturally-occurring food-derived chemopreventive agents. Our studies show that (−)-epigallocatechin-3-gallate (EGCG), a green teaderived polyphenol, acts to enhance the differentiation of normal human keratinocytes as evidenced by its ability to increase involucrin (hINV), transglutaminase type 1 (TG1) and caspase-14 gene expression. EGCG also stimulates keratinocyte morphological differentiation. These actions of EGCG are mediated via activation of a nPKC, Ras, MEKK1, MEK3, p38δ-ERK1/2 signaling cascade which leads to increased activator protein 1 (AP1) and CAATT enhancer binding protein (C/EBP) transcription factor expression, increased binding of these factors to DNA, and increased gene transcription. In contrast, apigenin, a dietary flavonoid derived from plants and vegetables, and curcumin, an agent derived from turmeric, inhibit differentiation by suppressing MAPK signal transduction and reducing API transcription factor level. Curcumin also acts to enhance apoptosis, although EGCG and apigenin do not stimulate apoptosis. In addition, all of these agents inhibit keratinocyte proliferation. These findings indicate that each of these diet-derived chemopreventive agents has a profound impact on normal human keratinocyte function and that they operate via distinct and sometimes opposing mechanisms. However, all are expected to act as chemopreventive agents. KeywordsEGCG; apigenin; curcumin; TPA; epidermis; involucrin; keratinocyte differentiation; apoptosis; chemoprevention; turmeric Keratinocyte differentiation and human involucrin gene expressionThe keratinocyte is the major cell type of the multilayered stratified squamous epithelium (the epidermis) that covers the body surface. To establish epidermal structure, keratinocytes in the basal layer undergo periodic cell division which gives rise to daughter cells that differentiate

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“…to produce the suprabasal epidermal layers (Nemes and Steinert, 1999). The epidermis provides protection against cancer-promoting agents present in the environment.…”

mentioning

confidence: 99%

Keratinocyte proliferation, differentiation, and apoptosis—Differential mechanisms of regulation by curcumin, EGCG and apigenin

Balasubramanian

Eckert

2007

Toxicology and Applied Pharmacology

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“…Depletion of intracellular Ca 2ϩ stores also regulates plasma membrane Ca 2ϩ entry channels. Ca 2ϩ ions have been suggested to be strongly associated with epidermal differentiation, barrier homeostasis, and formation of the cornified envelope (Watt, 1989;Nemes and Steinert, 1999). Thus, understanding Ca 2ϩ handling in keratinocytes of the DD disease model will be essential for understanding the molecular mechanisms involved in the progression of this disease.…”

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confidence: 99%

Up-Regulation of Transient Receptor Potential Canonical 1 (TRPC1) following Sarco(endo)plasmic Reticulum Ca²⁺ATPase 2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease

Pani

Cornatzer²,

Cornatzer

et al. 2006

MBoC

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The mechanism(s) involved in regulation of store operated calcium entry in Darier's disease (DD) is not known. We investigated the distribution and function of transient receptor potential canonical (TRPC) in epidermal skin cells. DD patients demonstrated up-regulation of TRPC1, but not TRPC3, in the squamous layers. Ca 2؉ influx was significantly higher in keratinocytes obtained from DD patients and showed enhanced proliferation compared with normal keratinocytes. Similar up-regulation of TRPC1 was also detected in epidermal layers of SERCA2 ؉/؊ mice. HaCaT cells expressed TRPC1 in the plasma membrane. Expression of sarco(endo)plasmic reticulum Ca 2؉ ATPase (SERCA)2 small interfering RNA (siRNA) in HaCaT cells increased TRPC1 levels and thapsigargin-stimulated Ca 2؉ influx, which was blocked by store-operated calcium entry inhibitors. Thapsigargin-stimulated intracellular Ca 2؉ release was decreased in DD cells. DD keratinocytes exhibited increased cell survival upon thapsigargin treatment. Alternatively, overexpression of TRPC1 or SERCA2-siRNA in HaCaT cells demonstrated resistance to thapsigargin-induced apoptosis. These effects were dependent on external Ca 2؉ and activation of nuclear factor-B. Isotretinoin reduced Ca 2؉ entry in HaCaT cells and decreased survival of HaCaT and DD keratinocytes. These findings put forward a novel consequence of compromised SERCA2 function in DD wherein up-regulation of TRPC1 augments cell proliferation and restrict apoptosis. We suggest that the anti-apoptotic effect of TRPC1 could potentially contribute to abnormal keratosis in DD. INTRODUCTIONDarier's disease (DD) is an autosomal dominant inherited skin disease, which is characterized by the loss of adhesion between epidermal cells and abnormal keratinization (Burge and Wilkinson 1992). Typical histological findings include focal areas of separation between suprabasal epidermal cells, unusual dyskeratosis with round dyskeratotic keratinocytes (Munro, 1992). Mutations in the sarco(endo)plasmic reticulum Ca 2ϩ ATPase (SERCA) isoform 2b (SERCA2b) gene leads to a loss of function, and these mutations have been shown to cause DD (Sakuntabhai et al., 1999). Most physiological systems are able to compensate for the loss of function of SERCA2b, possibly because of expression of other SERCA isoforms within those tissues (Dhitavat et al., 2003;Tavadia et al., 2004). However, of the multiple isoforms of SERCA1, -2, or -3, only SERCA2b is expressed in keratinocytes (Lytton and MacLennan, 1988;Ruiz-Perez et al., 1999). The mutated SERCA2 fails to sequester cytosolic Ca 2ϩ into the endoplasmic reticulum (ER) lumen, thereby disturbing the otherwise normal Ca 2ϩ homeostasis circuitry within the cells (Zhao et al., 2001;Ahn et al., 2003). Although oral retinoids, such as isotretinoin, have been shown to reduce hyperkeratosis (Burge and Wilkinson, 1992), the mechanism behind dysfunction of SERCA2 resulting in keratosis remains elusive.Ca 2ϩ is an integral signaling element that regulates numerous cellular processes (Clapham, 1995;Berridge e...

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“…Biological surface barrier function is conferred by epidermal cells, which in mammals and arthropods produce the stratum corneum and cuticle, respectively. The stratum corneum consists of layers of a highly cross-linked matrix of dead keratinocytes, proteins, and lipids (1). In contrast, the cuticle barrier of Drosophila and other insects consists of cross-linked lipids, proteins, and chitin (2).…”

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confidence: 99%

Phosphorylation of Grainy head by ERK is essential for wound-dependent regeneration but not for development of an epidermal barrier

Kim

McGinnis

2010

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

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Grainy head (GRH) is a key transcription factor responsible for epidermal barrier formation and repair, whose function is highly conserved across diverse animal species. However, it is not known how GRH function is reactivated to repair differentiated epidermal barriers after wounding. Here, we show that GRH is directly regulated by extracellular signal-regulated kinase (ERK) phosphorylation, which is required for wound-dependent expression of GRH target genes in epidermal cells. Serine 91 is the principal residue in GRH that is phosphorylated by ERK. Although mutations of the ERK phosphorylation sites in GRH do not impair its DNA binding function, the ERK sites in GRH are required to activate Dopa decarboxylase (Ddc) and misshapen (msn) epidermal wound enhancers as well as functional regeneration of an epidermal barrier upon wounding. This result indicates that the phosphorylation sites are essential for damaged epidermal barrier repair. However, GRH with mutant ERK phosphorylation sites can still promote barrier formation during embryonic epidermal development, suggesting that ERK sites are dispensable for the GRH function in establishing epidermal barrier integrity. These results provide mechanistic insight into how tissue repair can be initiated by posttranslational modification of a key transcription factor that normally mediates the developmental generation of that tissue.embryo | Drosophila | cuticle

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Bricks and mortar of the epidermal barrier

Cited by 502 publications

References 177 publications

Keratinocyte proliferation, differentiation, and apoptosis—Differential mechanisms of regulation by curcumin, EGCG and apigenin

Keratinocyte proliferation, differentiation, and apoptosis—Differential mechanisms of regulation by curcumin, EGCG and apigenin

Up-Regulation of Transient Receptor Potential Canonical 1 (TRPC1) following Sarco(endo)plasmic Reticulum Ca²⁺ATPase 2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease

Phosphorylation of Grainy head by ERK is essential for wound-dependent regeneration but not for development of an epidermal barrier

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Bricks and mortar of the epidermal barrier

Cited by 502 publications

References 177 publications

Keratinocyte proliferation, differentiation, and apoptosis—Differential mechanisms of regulation by curcumin, EGCG and apigenin

Keratinocyte proliferation, differentiation, and apoptosis—Differential mechanisms of regulation by curcumin, EGCG and apigenin

Up-Regulation of Transient Receptor Potential Canonical 1 (TRPC1) following Sarco(endo)plasmic Reticulum Ca2+ATPase 2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease

Phosphorylation of Grainy head by ERK is essential for wound-dependent regeneration but not for development of an epidermal barrier

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Up-Regulation of Transient Receptor Potential Canonical 1 (TRPC1) following Sarco(endo)plasmic Reticulum Ca²⁺ATPase 2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease