Epithelial Wound Healing Enhanced by Transforming Growth Factor-α and Vaccinia Growth Factor

Schultz, Gregory S.; White, Michael J. V.; Mitchell, Robert O.; Brown, Gregory L.; Lynch, Jenny; Twardzik, Daniel R.; Todaro, George J.

doi:10.1126/science.3492044

Cited by 347 publications

(122 citation statements)

References 20 publications

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“…4) demonstrating that both proteins are specific components of the JUN-dependent mitogenic program. In contrast to SDF-1 and PTN a number of other factors, such as EGF, TGFα and bFGF, which were shown to promote keratinocyte proliferation (Schultz et al, 1987;O'Keefe et al, 1988;Marchese et al, 1990), were not, or only weakly able to rescue the proliferation defect of keratinocytes in Jun -/-fibroblast co-cultures (see supplementary material Fig. S3), suggesting that only a subset of mitogenic cytokines is able to exhibit proliferationpromoting activity in this system.…”

Section: Discussionmentioning

confidence: 99%

Increased keratinocyte proliferation by JUN-dependent expression of PTN and SDF-1 in fibroblasts

Florin

Maas‐Szabowski

Werner

et al. 2005

Journal of Cell Science

106

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In skin, fibroblasts of the connective tissue play a decisive role in epidermal homeostasis and repair by contributing to the regulation of keratinocyte proliferation and differentiation. The AP-1 transcription factor subunit JUN plays a crucial role in this mesenchymal-epithelial interplay by regulating the expression of two critical paracrine-acting cytokines, keratinocyte growth factor (KGF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). We have performed gene expression profiling of wild-type and Jun–/– mouse embryonic fibroblasts to identify additional players involved in this complex network, and have found pleiotrophin (PTN) and the stromal cell-derived factor 1 (SDF-1) as novel JUN-regulated factors. Both cytokines are expressed by dermal fibroblasts in vivo, as shown by semi-quantitative RT-PCR and in situ hybridization on murine skin sections. Using a heterologous feeder layer co-culture system, we demonstrated that PTN and SDF-1 exert a mitogenic effect on primary human keratinocytes. Moreover, SDF-1-induced keratinocyte proliferation could be specifically inhibited by neutralizing antibodies against SDF-1 or its receptor, CXCR4. Consistent with its role in promoting keratinocyte growth, PTN was upregulated during cutaneous wound healing in vivo. Interestingly, co-cultivation with keratinocytes stimulated PTN expression but repressed SDF-1 production in fibroblasts, demonstrating the complexity of the paracrine regulatory cytokine networks that control skin homeostasis and regeneration.

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Section: Discussionmentioning

confidence: 99%

Increased keratinocyte proliferation by JUN-dependent expression of PTN and SDF-1 in fibroblasts

Florin

Maas‐Szabowski

Werner

et al. 2005

Journal of Cell Science

106

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“…After poration the cells were exposed to 5 mM glucose with or without 5 mM glucosamine for 3 atherogenesis. TGFa is normally found in arterioles (4) and is mitogenic for the arterial endothelium (18) (26), that do exhibit biologic activities toward vascular cells (27). Insulin did not, however, affect the transcription of TGFa in the aortic smooth muscle cells.…”

Section: Discussionmentioning

confidence: 99%

Glucose and glucosamine regulate growth factor gene expression in vascular smooth muscle cells.

McClain

Paterson

Roos

et al. 1992

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

178

110

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We have investigated the regulation of the expression of two growth factors found in vascular smooth muscle, transforming growth factor a (TGFa) and basic fibroblast growth factor (bFGF). Cells cultured in medium containing 30 mM glucose exhibited a 2-fold increase in TGFa mRNA and a 3-fold increase in bFGF mRNA compared with cells grown in normal (5.5 mM) glucose. Glucosamine was more potent than glucose, leading to a 6-fold increase in TGFa mRNA. TGFa protein levels were also increased by glucosamine treatment, and the predominant species present was the membrane-bound precursor form of TGFa. To examine further the regulation of growth factors by sugars, cultured rat aortic smooth muscle cells were transfected with a plasmid construct consisting of a 1.2-kilobase-pair fragment of the TGFa promoter linked to a luciferase reporter gene. Increasing the concentration ofglucose in the culture medium from 5.5 mM to 30 mM led to a rapid, 1.7-fold increase in the activity of the TGFa promoter. Glucosamine was much more potent than glucose in this stimulation, with 2 mM gluamine causing a 12-fold increase in TGFa promoter activity. Insulin had no effect on luciferase activity in either the presence or the absence of added sugars. The glucose response element of the TGFa gene maps to a 130-base-pair segment that includes three potential binding sites for the transcription factor Spl. We conclude that high glucose concentrations such as are reached in diabetes mellitus can stimulate the transcription of the genes for growth factors in vascular smooth muscle cells. This signaling pathway apparently involves the metabolism of glucose to glucosamine. This effect could be representative of nutritional regulation of a family of genes and could contribute to the toxicity of hyperglycemia and the vascular complications of diabetes.Vascular smooth muscle cell proliferation is an early event in the pathogenesis of atherosclerosis, and growth factors have been hypothesized to play an important role in the control of this process (1). For example, platelet-derived growth factor is expressed in atherosclerotic lesions and is found in macrophages in all phases ofthe development of those lesions (2). Growth factors synthesized by the vascular smooth muscle cells themselves may also be involved in the pathogenesis of vascular disease. Thus, the exposure of vascular smooth muscle cells to growth factors could be determined by the plasma concentration of a growth factor, by delivery from blood-derived cells, or by the production rate of the growth factor by cells within the vessel wall. To examine whether the synthesis of growth factors might be sensitive to environmental conditions, we studied two growth factors known to be expressed in vascular smooth muscle cells, transforming growth factor a (TGFa; refs. 3 and 4) and basic fibroblast growth factor (bFGF; refs. 5 and 6). In addition, because the promoter for the TGFa gene has been cloned and characterized (7, 8), we studied in more detail the transcriptional regulation of the ...

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“…ErbB signaling plays a very important role in the reepithelialization of skin wounds, as evidenced by acceleration of burn or partial-thickness wound healing by epidermal growth factor (EGF) (Brown et al, 1989), transforming growth factor-␣ (TGF-␣) (Schultz et al, 1987), heparin-binding EGF-like growth factor (HB-EGF) (Cribbs et al, 1998), and epiregulin (Draper et al, 2003). Corneal wound healing also is markedly inhibited after treatment with ErbB receptor tyrosine kinase inhibitors (RTKIs) (Nakamura et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…These events lead to activation of multiple signal transduction pathways via Src homology 2 (SH2)-and phosphotyrosine binding (PTB)-domain containing cytoplasmic proteins, ultimately affecting many cellular functions, including cell migration, proliferation, and differentiation (Hubbard et al, 1998;Hackel et al, 1999). We and others have demonstrated that human skin expresses ErbB1, ErbB2, and ErbB3, but little or no ErbB4 (Press et al, 1990;Prigent et al, 1992;De Potter et al, 2001;Stoll et al, 2001).ErbB signaling plays a very important role in the reepithelialization of skin wounds, as evidenced by acceleration of burn or partial-thickness wound healing by epidermal growth factor (EGF) (Brown et al, 1989), transforming growth factor-␣ (TGF-␣) (Schultz et al, 1987), heparin-binding EGF-like growth factor (HB-EGF) (Cribbs et al, 1998), and epiregulin (Draper et al, 2003). Corneal wound healing also is markedly inhibited after treatment with ErbB receptor tyrosine kinase inhibitors (RTKIs) (Nakamura et al, 2001).…”

mentioning

confidence: 99%

Autocrine Extracellular Signal-regulated Kinase (ERK) Activation in Normal Human Keratinocytes: Metalloproteinase-mediated Release of Amphiregulin Triggers Signaling from ErbB1 to ERK

Kansra

Stoll

Johnson

et al. 2004

MBoC

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ErbB signaling through extracellular signal-regulated kinase (ERK) has been implicated in regulating the expression of ErbB ligands in hyperproliferative skin disorders and wound healing. Here, we characterize the process of autocrine ERK activation in cultured normal human keratinocytes (NHKs) subjected to growth factor (GF) deprivation. Basal ERK phosphorylation was lower after 48 h than after 24 h of GF deprivation, and lowest at 30 -60 min after an additional medium change. ERK phosphorylation was markedly increased by low concentrations of epidermal growth factor (EGF) (0.2-1 ng/ml) that provoked only a limited increase in ErbB1 tyrosine phosphorylation and internalization. Basal ErbB tyrosine phosphorylation and ERK phosphorylation were inhibited by two different ErbB receptor tyrosine kinase inhibitors, by the ErbB1-specific neutralizing monoclonal antibody 225 IgG, by two different metalloproteinase inhibitors, and by neutralizing antibodies against amphiregulin (AR). In contrast, these responses were unaffected by neutralizing antibodies against other ErbB1 ligands or the ErbB2 inhibitors geldanamycin and AG825. The time course of autocrine ERK phosphorylation correlated with the appearance of soluble AR, and two different metalloproteinase inhibitors blocked AR release. These results define an amphiregulin-and ErbB1-dependent mechanism by which autocrine ERK activation is maintained in NHKs, even when ErbB1 autophosphorylation and internalization are limited. INTRODUCTIONThe mammalian c-ErbB family is comprised of four closely related receptor tyrosine kinases (RTKs) that interact hierarchically in response to multiple ErbB receptor ligands (Klapper et al., 2000;Olayioye et al., 2000). Ligand binding to the extracellular domain promotes receptor homo-and heterodimerization, resulting in phosphorylation of specific tyrosine residues on the cytoplasmic domain. These events lead to activation of multiple signal transduction pathways via Src homology 2 (SH2)-and phosphotyrosine binding (PTB)-domain containing cytoplasmic proteins, ultimately affecting many cellular functions, including cell migration, proliferation, and differentiation (Hubbard et al., 1998;Hackel et al., 1999). We and others have demonstrated that human skin expresses ErbB1, ErbB2, and ErbB3, but little or no ErbB4 (Press et al., 1990;Prigent et al., 1992;De Potter et al., 2001;Stoll et al., 2001).ErbB signaling plays a very important role in the reepithelialization of skin wounds, as evidenced by acceleration of burn or partial-thickness wound healing by epidermal growth factor (EGF) (Brown et al., 1989), transforming growth factor-␣ (TGF-␣) (Schultz et al., 1987), heparin-binding EGF-like growth factor (HB-EGF) (Cribbs et al., 1998), and epiregulin (Draper et al., 2003). Corneal wound healing also is markedly inhibited after treatment with ErbB receptor tyrosine kinase inhibitors (RTKIs) (Nakamura et al., 2001). Organ cultures of skin display many features of early wounds, including rapid keratinocyte cytoskeletal alterations, an early ...

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Epithelial Wound Healing Enhanced by Transforming Growth Factor-α and Vaccinia Growth Factor

Cited by 347 publications

References 20 publications

Increased keratinocyte proliferation by JUN-dependent expression of PTN and SDF-1 in fibroblasts

Increased keratinocyte proliferation by JUN-dependent expression of PTN and SDF-1 in fibroblasts

Glucose and glucosamine regulate growth factor gene expression in vascular smooth muscle cells.

Autocrine Extracellular Signal-regulated Kinase (ERK) Activation in Normal Human Keratinocytes: Metalloproteinase-mediated Release of Amphiregulin Triggers Signaling from ErbB1 to ERK

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