A Potential Role for Ceramide in the Regulation of Mouse Epidermal Keratinocyte Proliferation and Differentiation

Jung, EunMi; Griner, Richard D.; Mann-Blakeney, RaShawn; Bollag, Wendy B.

doi:10.1046/j.1523-1747.1998.00137.x

Cited by 39 publications

(34 citation statements)

References 38 publications

(48 reference statements)

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“…This ganglioside has been shown to decrease proliferation and stimulate terminal differentiation of these cells (18), which suggests the possibility that PLD activity is involved in keratinocyte differentiation. Our previous results also suggest a role for PLD in mediating growth inhibition and differentiation induction in keratinocytes (19). We hypothesized that (i) bradykinin and TPA activate PLD through PKC to assist in inducing keratinocyte differentiation, (ii) Stsp elicits its differentiative effects, at least in part, through an activation of PLD, and (iii) PLD activation is associated with keratinocyte differentiation.…”

Section: Introductionmentioning

confidence: 89%

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Sustained phospholipase D activation is associated with keratinocyte differentiation

et al. 1999

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Our previous results and data in the literature have suggested a potential role for phospholipase D (PLD) in the regulation of epidermal keratinocyte growth and differentiation. Therefore, we investigated the effect of agents reported to modulate keratinocyte growth and differentiation on PLD activation. The purported protein kinase C (PKC) 'inhibitor', staurosporine (Stsp), has been reported to activate PKC in keratinocytes, eliciting many of the same effects as active tumor promoters such as 12-Otetradecanoylphorbol-13-acetate (TPA). Stsp also induces a programmed pattern of differentiation similar to that seen in keratinocytes in vivo; TPA, on the other hand, appears to preferentially elicit markers consistent with late (granular) differentiation. In contrast, bradykinin is reported to stimulate keratinocyte proliferation. We found that these three agents had different effects on PLD activation in primary mouse epidermal keratinocytes. TPA increased PLD activity acutely and in a sustained fashion. In contrast, Stsp did not acutely activate PLD and inhibited acute TPA-induced activation of PLD. However, treatment of keratinocytes with Stsp for longer time periods (3-5 h) induced sustained PLD activation and this long-term effect was additive with that of TPA. Bradykinin activated PLD acutely but transiently. Both TPA and Stsp increased transglutaminase activity, a marker of late differentiation, whereas bradykinin had little or no effect on either cell proliferation or transglutaminase activity. These results suggest that a sustained activation of PLD is associated with the induction of keratinocyte differentiation. We hypothesize that PLD activity mediates late keratinocyte differentiation through generation of diacylglycerol and activation of specific PKC isoforms. Furthermore, we propose that the profound and immediate TPA-induced stimulation of PLD activity 'drives' the keratinocytes to late differentiation steps. However, the less efficacious (and more gradual) sustained activation of PLD by Stsp may allow a patterned differentiation more like that observed in skin.

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Section: Introductionmentioning

confidence: 89%

“…Transglutaminase activity was determined as in (19). Briefly, near-confluent keratinocytes were incubated for 18 h with the indicated concentrations of bradykinin, TPA or Stsp in SFKM.…”

Section: Measurement Of Transglutaminase Activitymentioning

confidence: 99%

Sustained phospholipase D activation is associated with keratinocyte differentiation

et al. 1999

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“…Protein quantities were determined using the Bio-Rad protein assay (Bio-Rad, Hercules, CA) with bovine serum albumin as standard. Transglutaminase activity was measured as the incorporation of [ 3 H]putrescine into dimethylated casein, as described previously (Jung et al, 1998).…”

Section: Methodsmentioning

confidence: 99%

Green Tea Polyphenols Induce Differentiation and Proliferation in Epidermal Keratinocytes

Hsu

Bollag²,

Lewis

et al. 2003

J Pharmacol Exp Ther

150

103

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The most abundant green tea polyphenol, epigallocatechin-3-gallate (EGCG), was found to induce differential effects between tumor cells and normal cells. Nevertheless, how normal epithelial cells respond to the polyphenol at concentrations for which tumor cells undergo apoptosis is undefined. The current study tested exponentially growing and aged primary human epidermal keratinocytes in response to EGCG or a mixture of the four major green tea polyphenols. EGCG elicited cell differentiation with associated induction of p57/KIP2 within 24 h in growing keratinocytes, measured by the expression of keratin 1, filaggrin, and transglutaminase activity. Aged keratinocytes, which exhibited low basal cellular activities after culturing in growth medium for up to 25 days, renewed DNA synthesis and activated succinate dehydrogenase up to 37-fold upon exposure to either EGCG or the polyphenols. These results suggest that tea polyphenols may be used for treatment of wounds or certain skin conditions characterized by altered cellular activities or metabolism.Green tea polyphenols (referred to as GTPPs, to include the four major polyphenols: epicatechin, epigallocatechin, epcatechin-3-gallate, and epigallocatechin-3-gallate (EGCG) have been identified to possess chemopreventive and apoptotic activity against certain cancers, whereas normal epidermal keratinocytes follow a survival pathway that has not been fully elucidated (Chen et al

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“…Studies in our laboratory also provide evidence for an involvement of PLD in keratinocyte growth inhibition and differentiation. Specifically, incubation of epidermal keratinocytes with bacterial PLD results in inhibition of proliferation and an increase in the activity of a marker of differentiation, transglutaminase (14). In addition, staurosporine and 12-O-tetradecanoylphorbol-13-acetate elicit sustained PLD activation and also induce transglutaminase activity in primary mouse keratinocytes.…”

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confidence: 99%

1,25-Dihydroxyvitamin D3 Induces Phospholipase D-1 Expression in Primary Mouse Epidermal Keratinocytes

Griner

Qin

Jung

et al. 1999

Journal of Biological Chemistry

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The skin is a dynamic organ consisting of the dermis and epidermis, with the latter continuously undergoing regeneration to replace cells lost through normal exposure to the environment. The epidermis is composed of several cell layers. The deepest layer, located at the dermal-epidermal junction, is the basal layer, consisting of the undifferentiated basal keratinocytes, which continuously proliferate. As the cells migrate up through the epidermis, keratinocytes undergo a distinct pattern of differentiation that is essential for the function of the skin as a protective barrier. This pattern is characterized by growth arrest and expression of the mature cytokeratins 1 and 10 in the first differentiated layer of the epidermis, the spinous layer. Early differentiation in the spinous layer is followed by late differentiation in the granular layer accompanied by expression of proteins, including the enzyme transglutaminase, that are essential for the formation of the cornified envelope and corneocytes. The corneocytes are terminally differentiated and constitute the outer layer of the epidermis, the cornified layer, which gives skin its resistance to mechanical stresses (for reviews, see Refs. 1 and 2). The mechanism by which 1,25(OH) 2 D 3 inhibits proliferation and stimulates differentiation is still unclear. This hormone is thought to function through the vitamin D receptor, a transcription factor affecting expression of genes possessing vitamin D response elements. However, the keratin 1 gene is the only keratinocyte differentiation marker known to possess a 1,25(OH) 2 D 3 response element (5, 6), and the expression of this marker is inhibited by 1,25(OH) 2 D 3 (7). In addition, 1,25(OH) 2 D 3 was recently shown to enhance the expression of several phosphoinositide-specific phospholipase C isoenzymes (8), the activity of which generates diacylglycerol (DAG). DAG, in turn, is known to regulate the activity of protein kinase C (PKC), and numerous data suggest the involvement of PKC in the regulation of keratinocyte growth and differentiation (reviewed in Refs. 1 and 9).Although PKC-activating DAG can be generated directly by phosphoinositide turnover via phospholipase C, such DAG can also be generated indirectly by an additional pathway. Diacylglycerol is generated by the combination of phospholipase D (PLD), which hydrolyzes phospholipids to generate phosphatidic acid (PA), and PA phosphohydrolase, which dephosphorylates PA to yield DAG (reviewed in Ref. 10). Indeed, in several cell systems, PLD activity has been shown to underlie at least

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A Potential Role for Ceramide in the Regulation of Mouse Epidermal Keratinocyte Proliferation and Differentiation

Cited by 39 publications

References 38 publications

Sustained phospholipase D activation is associated with keratinocyte differentiation

Sustained phospholipase D activation is associated with keratinocyte differentiation

Green Tea Polyphenols Induce Differentiation and Proliferation in Epidermal Keratinocytes

1,25-Dihydroxyvitamin D3 Induces Phospholipase D-1 Expression in Primary Mouse Epidermal Keratinocytes

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