1,25-Dihydroxyvitamin D3 upregulates the phosphatidylinositol signaling pathway in human keratinocytes by increasing phospholipase C levels.

Pillai, Sreekumar; Bikle, Daniel D.; Su, Mei-Jhy; Ratnam, Anita V.; Abe, Jun‐ichi

doi:10.1172/jci118075

Cited by 55 publications

(39 citation statements)

References 41 publications

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“…In our prior studies using isolated colonic membranes, 1,25(OH) 2 D 3 failed to directly stimulate PI hydrolysis (4), making the involvement of these predominantly membrane-associated isoforms of PI-PLC in this phenomenon less likely. In human keratinocytes, however, 1,25(OH) 2 D 3 increased both the mRNA and protein abundance of PLC-␤ 1 (30). Given these latter observations, and the inherent complexities of studying regulated PLC activity in reconstituted in vitro experiments, this issue will require further investigation.…”

Section: Discussionmentioning

confidence: 98%

1,25 dihydroxyvitamin D3 stimulates phospholipase C-gamma in rat colonocytes: role of c-Src in PLC-gamma activation.

Khare¹,

Bolt²,

Wali³

et al. 1997

J. Clin. Invest.

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Our laboratory has previously demonstrated that 1,25-dihydroxyvitamin D 3 (1,25[OH] 2 D 3 ) rapidly stimulated polyphosphoinositide (PI) hydrolysis, raised intracellular Ca 2 ϩ , and activated two Ca 2 ϩ -dependent protein kinase C (PKC) isoforms, PKC-␣ and -␤ II in the rat large intestine. We also showed that the direct addition of 1,25(OH) 2 D 3 to isolated colonic membranes failed to stimulate PI hydrolysis, but required secosteroid treatment of intact colonocytes, suggesting the involvement of a soluble factor. Furthermore, this PI hydrolysis was restricted to the basal lateral plasma membrane of these cells. In the present studies, therefore, we examined whether polyphosphoinositide-phospholipase C-␥ (PI-PLC-␥ ), a predominantly cytosolic isoform of PI-PLC, was involved in the hydrolysis of colonic membrane PI by 1,25(OH) 2 D 3 . This isoform has been shown to be activated and membrane-associated by tyrosine phosphorylation. We found that 1,25 (

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Section: Discussionmentioning

confidence: 98%

1,25 dihydroxyvitamin D3 stimulates phospholipase C-gamma in rat colonocytes: role of c-Src in PLC-gamma activation.

Khare¹,

Bolt²,

Wali³

et al. 1997

J. Clin. Invest.

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“…The addition of calcium leads to keratinocyte differentiation and the activation of several signaling pathways, one of which involves PLC-␥1, the predominant isoform of PLC in keratinocytes (13,14,16,17). However, it is not clear whether PLC-␥1 plays an essential role in the regulation of keratinocyte differentiation by calcium.…”

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confidence: 99%

Phospholipase C-γ1 Is Required for Calcium-induced Keratinocyte Differentiation

Xie

Bikle

1999

Journal of Biological Chemistry

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Phospholipase C-␥1 is the most abundant member of the phospholipase C family in keratinocytes and is induced by calcium. Phospholipase C-␥1, therefore, may be involved in the signal transduction system leading to calcium regulation of keratinocyte differentiation. To test this hypothesis, expression of phospholipase C-␥1 in human keratinocytes was blocked by transfecting cells with the antisense human phospholipase C-␥1 cDNA construct. These cells demonstrated a dramatic reduction in phospholipase C-␥1 protein level compared with the empty vector-transfected cells and a marked reduction in the mRNA and protein levels of the differentiation markers involucrin and transglutaminase following administration of calcium. Similarly, cotransfection of antisense phospholipase C-␥1 constructs with a luciferase reporter vector containing involucrin or transglutaminase promoters led to a substantial reduction in calcium-stimulated involucrin and transglutaminase promoter activities. Similar results were seen following treatment with a specific phospholipase C inhibitor U73122. To determine whether phospholipase C-␥1 regulated differentiation by controlling intracellular calcium, we examined the ability of antisense phospholipase C-␥1 to block the calcium-induced rise in intracellular calcium and found that it could. These findings indicate that phospholipase C-␥1 is a critical component of the signaling pathway mediating calcium regulation of keratinocyte differentiation via its mobilization of intracellular calcium.A variety of extracellular stimuli exert their physiologic effects by activating phospholipase C (PLC) 1 isozymes. PLC activation results in hydrolysis of phosphatidylinositol bisphosphate (PIP 2 ), a cell membrane phospholipid, generating inositol trisphosphate (IP 3 ), which releases calcium from intracellular stores, and diacylglycerol (DG), which activates protein kinase C. These second messengers subsequently activate a number of cellular reactions leading to changes in cell proliferation and differentiation (1, 2). There are at least three known types of PLC (-␤, -␥, and -␦), and each type has a number of subtypes (3, 4). The ␥-type enzymes are unique in that they contain SH 2 and SH 3 domains and are subject to activation by a number of growth factor receptors such as receptors for epidermal growth factor, nerve growth factor, and plateletderived growth factor (5-8).Human keratinocytes possess a functionally active inositol lipid signaling system (9 -12) that may play an essential role in keratinocyte differentiation (13-15). The addition of calcium leads to keratinocyte differentiation and the activation of several signaling pathways, one of which involves PLC-␥1, the predominant isoform of PLC in keratinocytes (13,14,16,17). However, it is not clear whether PLC-␥1 plays an essential role in the regulation of keratinocyte differentiation by calcium. To address this issue, we blocked PLC-␥1 production with antisense PLC-␥1 cDNA and inhibited its activity with a specific PLC inhibitor. Our results indicate...

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“…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.…”

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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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1,25-Dihydroxyvitamin D3 upregulates the phosphatidylinositol signaling pathway in human keratinocytes by increasing phospholipase C levels.

Abstract: These studies indicate that 1,25(OH)2D3 modulates the keratinocyte signal transduction pathway by induction of phospholipase isoenzymes, a previously undescribed action for this hormone. (J. Clin. Invest. 1995. 96:602-609.)

Cited by 55 publications

References 41 publications

1,25 dihydroxyvitamin D3 stimulates phospholipase C-gamma in rat colonocytes: role of c-Src in PLC-gamma activation.

1,25 dihydroxyvitamin D3 stimulates phospholipase C-gamma in rat colonocytes: role of c-Src in PLC-gamma activation.

Phospholipase C-γ1 Is Required for Calcium-induced Keratinocyte Differentiation

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

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