Regulation of the level and glycosylation state of plasminogen activator inhibitor type 2 during human keratinocyte differentiation.
Plasminogen activator inhibitor type 2 (PAI-2) is an unusual member of the serine proteinase inhibitor (serpin) family which has been implicated in the protection of cells from programmed cell death. Human epidermal keratinocytes synthesize large amounts of PAI-2 in two active forms: glycosylated and non-glycosylated. Calcium (Ca2+), a well-known inducer of numerous aspects of keratinocyte terminal differentiation, increases the steady-state levels of PAI-2 mRNA and protein. As the cultures become more differentiated due to longer incubation with Ca2+, the glycosylated form is preferentially elevated. Surprisingly, glycosylated as well as non-glycosylated PAI-2 remains predominantly cell-associated, in a trypsin-inaccessible form and thus most likely inside the cell. Tumor necrosis factor-alpha (TNF-alpha), an inflammatory mediator that induces some markers of keratinocyte differentiation, also increases PAI-2 mRNA and protein levels. Experiments using cultures in which protein kinase C has been downregulated suggest that Ca2+, but not TNF-alpha, acts at least partially through one or more isozymes of this kinase for induction of PAI-2. This is consistent with the finding that the effect of simultaneous addition of Ca2+ plus TNF-alpha is at least additive, compared with addition of either stimulant alone. These data demonstrate that the keratinocyte maintains multiple regulatory pathways for control of PAI-2 expression, at least one of which is related to terminal differentiation.
Department of Dermatology, University of Pennsylvania, Philadelphia 19106-6142, USA.
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Wang
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PJ
Jensen
D015415:Biomarkers; D002118:Calcium / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D006031:Glycosylation; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects*; D017396:Plasminogen Activator Inhibitor 2 / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D015415:Biomarkers; D017396:Plasminogen Activator Inhibitor 2; D014409:Tumor Necrosis Factor-alpha; D011493:Protein Kinase C; D002118:Calcium