The growth-promoting effect of KGF on limbal epithelial cells is mediated by upregulation of ΔNp63α through the p38 pathway

Cheng, Chien Chia; Wang, Der-Yuan; Kao, Ming Hui; Chen, Jan Kan

doi:10.1242/jcs.054791

Cited by 44 publications

(46 citation statements)

References 50 publications

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“…Previous studies have demonstrated that IGF-I and IGF-II can support the proliferation of keratinocytes [13] and, together with substance P, promote the growth of rabbit corneal epithelial cells [33,34]. A similar growth-promoting effect of KGF and HGF on limbal epithelial cells in the rabbit was described by Cheng et al [10]. In our mouse model, IGF-I, which induced the differentiation of LSC, did not support the proliferation of limbal cells, even though it was tested over a wide range of concentrations.…”

Section: Discussionsupporting

confidence: 63%

“…Among them, the genes coding for growth and differentiation factors represent a significant group. It was shown that the transforming growth factor-a (TGF-a), TGF-b, epidermal growth factor (EGF), hepatocyte growth factor (HGF), and fibroblast growth factor-b (FGF-b), which are produced by corneal epithelial cells, can modulate the proliferation and growth of cells on the ocular surface [10][11][12]. Another factor produced by the corneal epithelium, insulin-like growth factor-I (IGF-I), has been shown to support the proliferation of keratinocytes [13], enhance the production of the adherens-junction protein N-cadherin [14], stimulate the formation of the extracellular matrix [15], and increase the synthesis of collagen by keratinocytes [16].…”

Section: Introductionmentioning

confidence: 99%

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The Key Role of Insulin-Like Growth Factor I in Limbal Stem Cell Differentiation and the Corneal Wound-Healing Process

Trošan

Svobodová

Chudíčková

et al. 2012

Stem Cells and Development

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Limbal stem cells (LSC), which reside in the basal layer of the limbus, are thought to be responsible for corneal epithelial healing after injury. When the cornea is damaged, LSC start to proliferate, differentiate, and migrate to the site of injury. To characterize the signaling molecules ensuring communication between the cornea and LSC, we established a mouse model of mechanical corneal damage. The central cornea or limbal tissue was excised at different time intervals after injury, and the expression of genes in the explants was determined. It was observed that a number of genes for growth and differentiation factors were significantly upregulated in the cornea rapidly after injury. The ability of these factors to regulate the differentiation and proliferation of limbal cells was tested. It was found that the insulin-like growth factor-I (IGF-I), which is rapidly overexpressed after injury, enhances the expression of IGF receptor in limbal cells and induces the differentiation of LSC into cells expressing the corneal cell marker, cytokeratin K12, without any effect on limbal cell proliferation. In contrast, the epidermal growth factor (EGF) and fibroblast growth factor-b (FGF-b), which are also produced by the damaged corneal epithelium, supported limbal cell proliferation without any effect on their differentiation. Other factors did not affect limbal cell differentiation or proliferation. Thus, IGF-I was identified as the main factor stimulating the expression of IGF receptors in limbal cells and inducing the differentiation of LSC into cells expressing corneal epithelial cell markers. The proliferation of these cells was supported by EGF and FGF.

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Section: Discussionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

The Key Role of Insulin-Like Growth Factor I in Limbal Stem Cell Differentiation and the Corneal Wound-Healing Process

Trošan

Svobodová

Chudíčková

et al. 2012

Stem Cells and Development

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“…Limbal basal cell layers preferentially express certain structural proteins (vimentin, cytokeratin 14, 15 and 19), cell adhesion molecules (integrin α6, β1, The chemotactic signal for centripetal migration may be provided in the form of cytokines and/or the difference between the composition of extracellular matrix between the limbus and the cornea [59] . KGF, a paracrine hormone secreted by stromal cells, has been shown to enhance outgrowth in rabbit limbal explant culture on human amniotic membrane [60] . While the inflammatory cytokine interleukin-6 [61] , fibronectin [62] , and hyaluronan [63] , all of which are highly up-regulated upon injury, have been shown to play a role in drawing rabbit limbal cells towards the wound.…”

Section: Biochemical Characteristicsmentioning

confidence: 99%

Limbal stem cells: Central concepts of corneal epithelial homeostasis

Yoon¹

2014

WJSC

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A strong cohort of evidence exists that supports the localisation of corneal stem cells at the limbus. The distinguishing characteristics of limbal cells as stem cells include slow cycling properties, high proliferative potential when required, clonogenicity, absence of differentiation marker expression coupled with positive expression of progenitor markers, multipotency, centripetal migration, requirement for a distinct niche environment and the ability of transplanted limbal cells to regenerate the entire corneal epithelium. The existence of limbal stem cells supports the prevailing theory of corneal homeostasis, known as the XYZ hypothesis where X represents proliferation and stratification of limbal basal cells, Y centripetal migration of basal cells and Z desquamation of superficial cells. To maintain the mass of cornea, the sum of X and Y must equal Z and very elegant cell tracking experiments provide strong evidence in support of this theory. However, several recent studies have suggested the existence of oligopotent stem cells capable of corneal maintenance outside of the limbus. This review presents a summary of data which led to the current concepts of corneal epithelial homeostasis and discusses areas of controversy surrounding the existence of a secondary stem cell reservoir on the corneal surface

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“…The adenovirus vector, designated Ad-DNp63, was constructed as described before. 25 A recombinant adenovirus carrying only GFP was used as a control. Briefly, viral stock was diluted into 0.5 ml culture medium and added to the culture dishes.…”

Section: Infection Of Recombinant Adenovirus Vectorsmentioning

confidence: 99%

“…A range of PCR reaction cycles (25,27,30,33,36,39 and 40 cycles) were performed to evaluate the relative abundance of p63 transcripts. Diluted cDNA (1:4; 12.5 ng/50 ml PCR reaction) undergoing 25 and 30 PCR cycles was observed to be within the logarithmic phase of amplification and yielded reproducible results with the primers used.…”

Section: Semi-quantitative Pcrmentioning

confidence: 99%

Resveratrol-induced p53-independent apoptosis of human nasopharyngeal carcinoma cells is correlated with the downregulation of ΔNp63

et al. 2010

Cancer Gene Ther

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DNp63, the N-terminal truncated isoform of p63, has been found to be overexpressed in several human epithelial cancers, including nasopharyngeal carcinomas (NPCs), suggesting a function in carcinogenesis. Trans-resveratrol (RSV) has been shown to exert proapoptotic activities through a p53-dependent or p53-independent pathway in various cancer cells. However, the effects of RSV on NPC are still unexplored. In this study, we investigated the apoptotic effects of RSV on DNp63-overexpressing NPC cell lines. We showed that RSV (12-100 mM) induced dose-dependent growth suppression, cell-cycle arrest in the S phase and caspasedependent apoptosis in NPC-TW076 and NPC-TW039 cells. The RSV effect was accompanied by the downregulation of DNp63 and the upregulation of p53 protein in a dose-dependent manner. By using small-interfering RNA (siRNA) technology, we found that the targeted silencing of DNp63 induced apoptosis and sensitized the NPC cells to RSV-induced apoptosis through caspase-3 activation, whereas suppression of p53 by siRNA did not inhibit RSV-induced apoptosis. Furthermore, transfection with p53 siRNA or pretreatment with caspase inhibitors (Z-VAD-fmk or Z-DEVD-fmk) had no influence on the RSV downregulation of DNp63. Interestingly, ecoptic expression of DNp63 did not significantly block RSV-induced cell death and was also downregulated after RSV treatment. Downregulation of DNp63 by RSV was shown to occur at the mRNA transcript and post-translational levels. Importantly, RSV enhanced chemotheraptic drug-induced apoptosis in NPC and two human carcinoma cell lines, HT1376 and Hep3B cells. These results suggested that DNp63, but not p53, is a molecular target of RSV-induced apoptosis and the regulation of DNp63 expression by RSV may provide a therapeutic effect of RSV in human NPC.

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The growth-promoting effect of KGF on limbal epithelial cells is mediated by upregulation of ΔNp63α through the p38 pathway

Cited by 44 publications

References 50 publications

The Key Role of Insulin-Like Growth Factor I in Limbal Stem Cell Differentiation and the Corneal Wound-Healing Process

The Key Role of Insulin-Like Growth Factor I in Limbal Stem Cell Differentiation and the Corneal Wound-Healing Process

Limbal stem cells: Central concepts of corneal epithelial homeostasis

Resveratrol-induced p53-independent apoptosis of human nasopharyngeal carcinoma cells is correlated with the downregulation of ΔNp63

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