Plasminogen/plasmin regulates c-fos and egr-1 expression via the MEK/ERK pathway.

In this study, we showed that plasminogen (Plg) and plasmin (Pla) bind to lysine-binding sites on cell surface and trigger a signaling pathway that activates the mitogen-activated protein kinase (MAPK) MEK and ERK1/2, which in turn leads to the expression of the primary response genes c-fos and early growth response gene egr-1. Our data show that the Plg/Pla-stimulated steady-state mRNA levels of both genes reached a maximum by 30 min and then returned to basal levels by 1h. The gene induction was sensitive to both pharmacological and genetic inhibition of MEK. Leupeptin, a serine protease inhibitor, suppressed Pla but not Plg-induced c-fos and egr-1 expression, emphasizing the role played by the serine protease activity associated with Pla. Pre-incubation with cholera toxin completely blocked the Plg/Pla-induced gene expression, suggesting that another signaling pathway, which recruits G protein-coupled receptors, may also be involved. Furthermore, Plg/Pla also stimulated AP-1 and EGR-1 DNA-binding activities, which were abrogated by pharmacological inhibition of MEK. Altogether, these results suggest that Plg/Pla stimulates c-fos and egr-1 expression via activation of the MEK/ERK pathway.

Localization of plasminogen in the extracellular matrix of hamster eggs: exogenous activation by streptokinase.

The plasminogen activator (PA)/plasminogen/plasmin proteolytic system has begun to be taken into account in the fertilization process. In this study, we demonstrated the presence of plasminogen in the extracellular matrix (ECM) of hamster oocytes by indirect immunofluorescence and immunoperoxidase assays using human anti-plasminogen. Plasminogen appeared first on the zona pellucida (ZP) of ovarian oocytes and later on the plasma membrane (PM) of oviducal eggs. This would suggest that oviducal oocytes modulate the expression of plasminogen binding sites on the PM. Human plasminogen as well as that of other species, known to be activated by streptokinase (SK), is rapidly converted to a plasmin-SK complex. We demonstrated the rapid formation of a SK-plasminogen complex that yields plasmin in the blood plasma of hamsters. Both the in vivo and in vitro SK treatment of eggs from superovulated female hamsters caused a decreased in the ZP dissolution time (ZPdt), probably either due to the proteolytic effect of plasmin or due to the SK-Plasminogen. Extracellular proteolysis assays carried out on agar-casein plates confirmed the proteolytic activity of SK-incubated eggs; the controls, on the contrary, failed to display a halo. These studies show that (1) superovulated hamster eggs contain plasminogen in their ECM, (2) oviducal eggs exhibit plasminogen on their PMs, indicating the presence of their corresponding binding sites, (3) in hamsters, SK, a non-enzymatic exogenous protein would be capable of activating ECM plasminogen to plasmin, and (4) the complex SK-plasminogen and/or the plasmin are capable of changing the ZPdt with alpha-chymotrypsin.

Oral lesions indicative of plasminogen deficiency (hypoplasminogenemia)

Background. Gingival overgrowth with ulceration has recenthy been recorded in 4 reports: (1) our report of a British patient with ligneous conjunctivitis in whom the gingival lesions appeared to be related to tranexamic acid-an antifibrinolytic agent; (2) a report of 2 Turkish patients and an Italian patients with mainly gingival lesions; (3) our report of 5 Turkish patient with mainly gingival lesions; and (4) a report of 3 Turkish cases, which also were associted with gingival lesions and alveolar bone loss. These patients all had gingival swellings, and a minority had conjunctival involvement similar to ligneous conjunctivitis, although material seen on the gingival biopsy stained for fibrin but failed to stain for amyloid. Methods. We have examinated 6 more patients who exhibited gingival swelling caused by amyloidaceous deposits that stained only for fibrin, and we assayed their plasminogen levels. Results. The plasminogen functional activity assayed in these 6 additional patients, and in 2 of the 5 patients previously reported by us, was significantly reduced. Conclusions. Gingival overgrowth with ulceration appears to be a new complication caused by plasminogen deficiency; it also appears to be related to ligneous conjunctivitis in some cases

Homozygous type I plasminogen deficiency

Homozygous type I plasminogen (Plg) deficiency has not been described in human subjects so far. Ligneous conjunctivitis is a rare and unusual form of chronic pseudomembranous conjunctivitis of unknoen etiology. Here we report for the first time on homozygous type I Plg deficiency in three unrelated female patients who suffered from ligneous conjunctivitis and additional pseudomembranous lesions of other mucous membranes. The disease is caused by massive fibrin depositions within the "extravascular space" of mucous membranes because of absent clearence by plasmin. Infusions of albumin, frech frozen plasma, or Lys-plasminogen (Lys-Plg) into two of the three patients revealed normal Plg activation capacity in these patients. The absence of fibrinolytic activity could therefore be shown to be due to Plg deficiency. Similar studies in the third patients have not been completed. In the two patients studied so far, infusions of Lys-Plg resulted in pronpt and adequate Plg recovery with a short half-life and high amounst of plasmin-antiplasmin complexes and D-dimer. One patient additionally revealed and inherited partial factor XII deficiency. Functionally, this factor XII deficiency did not interfere with Plg activation. However, there may be a pathway of Plg activation in this patient via the prekallikrein C1-INH system

Relación entre el activador del plasminógeno tipo urocinasa y el cáncer: mecanismo de regulación y control / Relation between urokinase-type plasminogen activator and cancer mechanims of regulation and control

Son analizados y discutidos los aspectos fisiológicos, bioquímicos y reguladores de la formación de plasmina por el activador de plasminógeno tipo urocinasa (uAP), así como su relación con el cáncer. En el cáncer, la activación del plasminógeno en la superficie celular ha mostrado ser esencial en la degradación de la matriz extracelular, en la disolución de la membrana basal, en los procesos de invasión y en las metástasis. La capacidad de las células para producir plasmina sobre su superficie celular depende de la presencia de uAP y del receptor del plasminógeno; ambos son las base de la regulación del sistema activante del plasminógeno in vivo

Estudo comparativo da atividade fibrinolítica do plasma de rato em fibrina humana, bovina e murina / A comparative study of fibrinolytic activity of rat plasm in human, bovine e murine fibrin

Vários estudos mostram que o sangue humano lisa espontaneamente enquanto o sangue de outras espécies animais necessitam de altas concentraçöes de ativadores. Nossos resultados mostram que o plasma de rato näo tratado é capaz de lisar a fibrina murina, mas näo a fibrina humana ou bovina. Porém, quando tratamos estes animais com adrenalina, um conhecido ativador do sistema fibrinolítico, o plasma destes animais é capaz de digerir a fibrina humana e bovina. Estes resultados mostram que o uso da fibrina adequada para cada espécie de animal estudado pode evitar resultados discrepantes nos diferentes laboratórios que estudam atividade fibrinolítica