Vitamin D enhances mitogenesis mediated by keratinocyte growth factor receptor in keratinocytes

Gamady, Anat; Koren, Ruth; Ron, Dina; Liberman, Uri; Ravid, Amiram

doi:10.1002/jcb.10508

Cited by 18 publications

(15 citation statements)

References 49 publications

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“…Erk1/2 Activation and Mitogenic Assays-HaCaT cultures were serum-starved in the presence of AG 1478 (0.5 M; Alexis) as described previously (46). For mitogenic assays, cells were stimulated with increasing concentrations of FGF7 for 16 h. H]Thymidine (ICN) was added for 6 h, and thymidine incorporation was determined using a Wallac-1049 liquid scintillation counter (47).…”

Section: Methodsmentioning

confidence: 99%

Targeting Perlecan in Human Keratinocytes Reveals Novel Roles for Perlecan in Epidermal Formation

Sher

Zisman‐Rozen

Eliahu

et al. 2006

Journal of Biological Chemistry

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Heparin-binding growth factors are crucial for the formation of human epidermis, but little is known about the role of heparan sulfate proteoglycans in this process. Here we investigated the role of the heparan sulfate proteoglycan, perlecan, in the formation of human epidermis, by utilizing in vitro engineered human skin. By disrupting perlecan expression either in the dermis or the epidermis, we found that epidermally derived perlecan is essential for epidermal formation. Perlecan-deficient keratinocytes formed a strikingly thin and poorly organized epidermis because of premature apoptosis and failure to complete their stratification program. Exogenous perlecan fully restored epidermal formation. Perlecan deposition in the basement membrane zone correlated with formation of multilayered epidermis. Perlecan deficiency, however, had no effect on the lining and deposition of major basement membrane components as was evident by a continuous linear staining of laminin and collagen IV. Similarly, perlecan deficiency did not affect the distribution of ␤1 integrin. Addition of the perlecan ligand, fibroblast growth factor 7, protected perlecan-deficient keratinocytes from cell death and improved the thickness of the epidermis. Taken together, our results revealed novel roles for perlecan in epidermal formation. Perlecan regulates both the survival and terminal differentiation steps of keratinocytes. Our results suggested a model whereby perlecan regulates these processes via controlling the bioavailability of perlecan-binding soluble factors involved in epidermal morphogenesis.Skin is the largest organ of the body. It serves as a shield against microorganism invasion and UV radiation, prevents dehydration, regulates body temperature, and is a part of the immune system (1). It consists of two distinct tissues, epidermis and dermis that are separated by a basement membrane (BM). 4 The dermis is a dense collagen-rich connective tissue that provides the support and nourishment to the overlying epidermis. It is mainly composed of fibroblasts that synthesize and secrete the various extracellular matrix (ECM) components (2). The epidermis is made primarily of keratinocytes that form a stratified squamous epithelium. It consists of multiple layers exhibiting distinct morphology and function. From the innermost to the outermost layers, they are the basal, spinous, granular, and cornified strata (3). Throughout adult life, the epidermis undergoes continuous self-renewal through proliferation of the basal cells, the only cells of the epidermis with the ability to proliferate. The keratinocytes undergo terminal differentiation as they leave the basal layer and move upward through the suprabasal layers toward the tissue surface, where they die and are sloughed off (3). This process makes the skin an excellent model system to study the coordinated regulation of cell proliferation, cell differentiation, and cell death. The formation of the mature epidermis is regulated by cross-talk with the adjacent connective tissue through a netw...

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Section: Methodsmentioning

confidence: 99%

Targeting Perlecan in Human Keratinocytes Reveals Novel Roles for Perlecan in Epidermal Formation

Sher

Zisman‐Rozen

Eliahu

et al. 2006

Journal of Biological Chemistry

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“…2A). Further, we tested the effect of pCD and AP on proliferation of HaCaT keratinocytes in serum-free condition (Gamady et al, 2003;Grossman et al, 2004;Pozzi et al, 2004). The growth of cells in 10% FCS was taken as positive control and cell growth in medium without FCS served as a negative control.…”

Section: Pcd Acts As An Autocrine Mitogen On Keratinocytesmentioning

confidence: 99%

Procathepsin D secreted by HaCaT keratinocyte cells – A novel regulator of keratinocyte growth

Vashishta¹,

Ohri²,

Větvičková³

et al. 2007

European Journal of Cell Biology

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Procathepsin D (pCD), the precursor form of lysosomal aspartic protease, is overexpressed and secreted by various carcinomas. The fact that secreted pCD plays an essential role in progression of cancer has been established. In this study, we describe substantial secretion of pCD by the human keratinocyte cell line HaCaT, under serum-free conditions. Moreover, exogenous addition of purified pCD enhanced the proliferation of HaCaT cells. The proliferative effect of pCD was inhibited by a monoclonal antibody against the activation peptide (AP) of pCD. Treatment of HaCaT cells with pCD or AP led to the secretion of a set of cytokines that might promote the growth of cells in a paracrine manner. The role of secreted pCD and its mechanism of action were studied in a scratch wound model and the presence of pCD and AP enhanced regeneration, while this effect was reversed by the addition of anti-AP antibody. Expression and secretion of pCD was upregulated in HaCaT cells exposed to various stress conditions. Taken together, our results strongly suggest that the secretion of pCD is not only linked to cancer cells but also plays a role in normal physiological conditions like wound healing and tissue remodeling.

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“…Growth factors, including epidermal growth factor (EGF) and keratinocyte growth factor, act in autocrine and paracrine manners to stimulate their cognate receptors, leading to activation of the various survival signaling pathways. [1][2][3][4][5][6] Opposed are signaling pathways leading to cell death such as c-Jun N-terminal kinase (JNK) and p38 MAPK. [7][8][9] We and others have shown that p38 MAPK and JNK are activated in keratinocytes by various stresses including UVB, oxidative stress, heat shock, proinflammatory cytokines and osmotic shock.…”

Section: Introductionmentioning

confidence: 99%

Programmed cell death of stressed keratinocytes and its inhibition by vitamin D: The role of death and survival signaling pathways

2006

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The epidermis is confronted with multiple environmental and pathophysiological stresses. This study shows that TNFalpha, oxidative stress, hyperosmotic and heat shock induced both caspase-dependent and independent cell death in human HaCaT keratinocytes. The hormonal form of vitamin D, 1,25(OH)2D3, which is an autocrine hormone in the epidermis, protected the cells from all the examined stresses and pathways leading to cell death. We aimed to define the signaling pathways that determine the life-death balance of stressed keratinocytes and participate in their protection by 1,25(OH)2D3. As assessed by employing specific inhibitors, the survival pathways mediated by the EGF receptor, ERK, PI-3K or Src kinase, or basal transcriptional activity are important for unstressed cell survival. However, only the EGF receptor, PI-3K and the Src kinase pathways mediate the survival of stressed cells in a stimulus-specific manner. Inhibition of the p38 and/or the JNK death pathways reduced caspase activation induced by oxidative stress, hyperosmotic shock and TNFalpha. The protective effect of 1,25(OH)2D3 was not mediated by the examined survival pathways. 1,25(OH)2D3 inhibited the stress-induced activation of p38 and JNK. Since mimicking this effect by pharmacological inhibition resulted in the attenuation of caspase activation, we infer that these pathways are involved in keratinocyte protection by 1,25(OH)2D3.

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Vitamin D enhances mitogenesis mediated by keratinocyte growth factor receptor in keratinocytes

Cited by 18 publications

References 49 publications

Targeting Perlecan in Human Keratinocytes Reveals Novel Roles for Perlecan in Epidermal Formation

Targeting Perlecan in Human Keratinocytes Reveals Novel Roles for Perlecan in Epidermal Formation

Procathepsin D secreted by HaCaT keratinocyte cells – A novel regulator of keratinocyte growth

Programmed cell death of stressed keratinocytes and its inhibition by vitamin D: The role of death and survival signaling pathways

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