Urokinase- and Tissue-Type Plasminogen Activators in Keratinocytes During Wound Reepithelialization In Vivo

Grøndahl-Hansen, J.; Lund, Leif R.; Ralfkiær, Elisabeth; Ottevanger, V; Danø, Keld

doi:10.1111/1523-1747.ep12461511

Cited by 209 publications

(96 citation statements)

References 62 publications

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“…the matrix during wound healing (68). Plasminogen-deficient mice depict a delay in wound healing, as evidenced by decreased migration of keratinocytes from the wound edges and their decreased ability to proteolytically dissect their way through the matrix (69,70).…”

Section: Interaction Among the Mirna Predicted Targets And Altered Womentioning

confidence: 99%

Downregulation of miRNAs during Delayed Wound Healing in Diabetes: Role of Dicer

Bhattacharya

Aggarwal

Singh

et al. 2015

Mol Med

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Delayed wound healing is a major complication associated with diabetes and is a result of a complex interplay among diverse deregulated cellular parameters. Although several genes and pathways have been identified to be mediating impaired wound closure, the role of microRNAs (miRNAs) in these events is not very well understood. Here, we identify an altered miRNA signature in the prolonged inflammatory phase in a wound during diabetes, with increased infiltration of inflammatory cells in the basal layer of the epidermis. Nineteen miRNAs were downregulated in diabetic rat wounds (as compared with normal rat wound, d 7 postwounding) together with inhibited levels of the central miRNA biosynthesis enzyme, Dicer, suggesting that in wounds of diabetic rats, the decreased levels of Dicer are presumably responsible for miRNA downregulation. Compared with unwounded skin, Dicer levels were significantly upregulated 12 d postwounding in normal rats, and this result was notably absent in diabetic rats that showed impaired wound closure. In a wound-healing specific quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) array, 10 genes were significantly altered in the diabetic rat wound and included growth factors and collagens. Network analyses demonstrated significant interactions and correlations between the miRNA predicted targets (regulators) and the 10 wound-healing specific genes, suggesting altered miRNAs might fine-tune the levels of these genes that determine wound closure. Dicer inhibition prevented HaCaT cell migration and affected wound closure. Altered levels of Dicer and miRNAs are critical during delayed wound closure and offer promising targets to address the issue of impaired wound healing.

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Section: Interaction Among the Mirna Predicted Targets And Altered Womentioning

confidence: 99%

Downregulation of miRNAs during Delayed Wound Healing in Diabetes: Role of Dicer

Bhattacharya

Aggarwal

Singh

et al. 2015

Mol Med

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“…This is much higher than the approximately 30 pM found in blood plasma 1371. Studies by immuno-histochemistry and in situ hybridization have, however, shown that the expression of uPA in tissue-remodeling events is often highly localized to specific areas, such as the migrating keratinocytes at wound edges [38,391 and the interface between cancer cells and stromal cells at invasive foci in tumors 140-421. uPAR is expressed in the same areas, often being produced by different cell types, indicating a cellular interplay in regulation of plasminogen activation [42,431. These findings point to large differences in the local concentration of uPA and suggest that high concentrations occur in areas where the physiological interaction with uPAR takes place.…”

Section: Discussionmentioning

confidence: 99%

Cell‐Surface Acceleration of Urokinase‐Catalyzed Receptor Cleavage

Høyer‐Hansen

Ploug

Behrendt

et al. 1997

European Journal of Biochemistry

106

127

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The urokinase-type plasminogen activator (uPA) binds to a specific cell-surface receptor, uPAR. On several cell types uPAR is present both in the full-length form and a cleaved form, uPAR(2+3), which is devoid of binding activity. The formation of uPAR(2+3) on cultured U937 cells is either directly or indirectly mediated by uPA itself. In a soluble system, uPA can cleave purified uPAR, but the low efficiency of this reaction has raised doubts as to whether uPA is directly responsible for uPAR cleavage on the cells. We now report that uPA-catalyzed cleavage of uPAR on the cell surface is strongly favored relative to the reaction in solution. The time course of uPA-catalyzed cleavage of cell-bound uPAR was studied using U937 cells stimulated with phorbol 12-myristate 13-acetate. Only 30 min was required for 10 nM uPA to cleave 50% of the cell-bound uPAR. This uPA-catalyzed cleavage reaction was inhibited by a prior incubation of the cells with uPA inactivated by diisopropyl fluorophosphate, demonstrating a requirement for specific receptor binding of the active uPA to obtain the high-efficiency cleavage of cellbound uPAR. Furthermore, amino-terminal sequence analysis revealed that uPAR(2 + 3), purified from U937 cell lysates, had the same amino termini as uPAR(2+3), generated by uPA in a purified system. In both cases cleavage had occusred at two positions in the hinge region connecting domain 1 and 2, between Arg83-Ah84 and Arg89-Ser90, respectively. The uPA-catalyzed cleavage of uPAR is a new negativefeedback regulation mechanism for cell-surface plasminogen activation. We propose that this mechanism plays a physiological role at specific sites with high local concentrations of uPA, thus adding another step to the complex regulation of this cascade reaction.

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“…However, since the activated vascular cells express uPA and uPAR, then the cells should be able to remove PAI-1 from the matrix and expose the cryptic integrin adhesion sites on vitronectin. Finally, since uPAR expression is localized to the leading edge of the migrating cells (34), this permits cells expressing uPA and uPAR to preferentially form new adhesion complexes at the apex of the moving angiogenic front, thus imparting directionality to vascular cell migration.…”

Section: Tumor Sections Treated With Pbs (A D G) Partially Inactivmentioning

confidence: 99%

Plasminogen Activator Inhibitor-1 Regulates Tumor Growth and Angiogenesis

McMahon¹,

Petitclerc²,

Stefansson³

et al. 2001

Journal of Biological Chemistry

247

190

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Elevated expression of plasminogen activator inhibitor-1 (PAI-1) in tumors is associated with a poor prognosis in many cancers. Reduced tumor growth and angiogenesis have also been reported in mice deficient in PAI-1. These results suggest that PAI-1 may be required for efficient angiogenesis and tumor growth. In the present study, we demonstrate that PAI-1 can both enhance and inhibit the growth of M21 human melanoma tumors in nude mice and that this appears to be due to PAI-1 regulation of angiogenesis. Quantitative analysis of angiogenesis in a Matrigel implant assay indicated that in PAI-1 null mice angiogenesis was reduced ϳ60% compared with wild-type mice, while in mice overexpressing PAI-1, angiogenesis was increased nearly 3-fold. Furthermore, addition of PAI-1 to implants in wild-type mice enhanced angiogenesis up to 3-fold at low concentrations but inhibited angiogenesis nearly completely at high concentrations. Together, these data demonstrate that PAI-1 is a potent regulator of angiogenesis and hence of tumor growth and suggest that understanding the mechanism of this activity may lead to the development of important new therapeutic agents for controlling pathologic angiogenesis.

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Urokinase- and Tissue-Type Plasminogen Activators in Keratinocytes During Wound Reepithelialization In Vivo

Cited by 209 publications

References 62 publications

Downregulation of miRNAs during Delayed Wound Healing in Diabetes: Role of Dicer

Downregulation of miRNAs during Delayed Wound Healing in Diabetes: Role of Dicer

Cell‐Surface Acceleration of Urokinase‐Catalyzed Receptor Cleavage

Plasminogen Activator Inhibitor-1 Regulates Tumor Growth and Angiogenesis

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