Disease relevance of Plau

• Our results indicated that altered expression of PAI-1, uPA, and uPAR in diabetic nephropathy was associated with mesangial expansion and that the beneficial effects of ACE-I may be at least associated with such expression [1].
• Urokinase plasminogen activator (uPA) is a serine protease which has frequently been implicated in the process of tumor cell invasion and metastasis [2].
• By contrast, uPA RNA (and enzyme) levels were elevated by up to 70-fold in metastatic clones of dimethylbenz(a)anthracene-induced rat mammary adenocarcinoma (DMBA-8) due to predominantly posttranscriptional mechanisms [2].
• CONCLUSIONS: We concluded that PG and PL had significant adhesion- and abscess-reducing effects and may act by modulating fibrinolytic capacity of uPA and/or tPA produced from macrophages in a rat peritonitis model [3].
• These results underscore the utility of anti-proteolytic agents (B-428) in addition to standard hormone therapy (TAM) in advanced breast cancer patients where the uPA/uPAR system plays a key role in tumor progression [4].

Psychiatry related information on Plau

• We show that doxycycline-dependent over-expression of uPA in these regions yields a 10- to 12.3-fold increase in locomotor activity after cocaine administration [5].

High impact information on Plau

• FAEEs reduced the activity of the serine protease, plasmin, and that of the uPA [6].
• In vivo administration of FAEEs reduced plasmin and uPA activities and increased ECM protein levels in pancreas [6].
• As with tPA synthesis in the rat, uPA production by mouse granulosa cells is induced by gonadotropins, dibutyryl cAMP, and prostaglandin E2 [7].
• However, dexamethasone, a drug which has no effect on tPA synthesis in rat cells inhibits uPA synthesis in the mouse [7].
• Rat follicular fluid contained only tPA, and mouse follicular fluid only uPA, indicating that in vivo, granulosa cells from the two species are secreting different enzymes [7].

Chemical compound and disease context of Plau

• CONCLUSION: We concluded that 0.5% polysaccharide derived from PG and PL was the optimal concentration in preventing adhesion and abscess formation and may act by modulating activity of uPA and TNF-alpha in a rat peritonitis model [8].
• The glucocorticoid dexamethasone was observed to decrease urokinase plasminogen activator (uPA) RNA levels from within 1 h of treatment of MAT 13762 mammary adenocarcinoma cells [9].
• These studies demonstrate the production of a mitogenic NH2-terminal fragment of uPA by a human prostatic cancer cell line which may be of importance in the pathogenesis of osteoblastic metastases [10].
• Octreotide, acting on TGF-beta1, uPA, and MMP-1 production, may be a useful agent for fibrosis resolution [11].

Biological context of Plau

• The urokinase-type plasminogen activator (uPA) system has been implicated in cell migration, angiogenesis, extracellular matrix synthesis and tissue remodelling [12].
• DNA synthesis was assessed by measuring the incorporation of [3H]-thymidine into cellular DNA fraction. tPA, uPA and type-1 plasminogen activator inhibitor (PAI-1) gene expressions were measured by Northern blotting [13].
• These results suggest that in addition to gene transcription, posttranscriptional events localized in the nucleus and cytoplasm are key determinants of uPA gene activation in rat mammary adenocarcinomas [2].
• Nuclear run-on assays and RNA half-life estimations indicated that metastatic MAT 13762 rat mammary adenocarcinoma cells expressed 3.5-fold higher levels of uPA RNA than a nonmetastatic derivative (J-clone), due to a combined increase in uPA gene transcription and cytoplasmic RNA stability [2].
• Whereas uPA transcript and protein levels were highest at the earliest stage of follicular growth examined and decreased markedly before the expected time of ovulation, the opposite was true for uPAR [14].

Anatomical context of Plau

• Interestingly, uninjured control tendons expressed uPA mRNA and protein, but little uPAR transcripts and protein [12].
• On day 14 following Achilles tendon division, uPA receptor protein increased 12.6-fold (p<0.001) while uPA itself increased only 1.3-fold (p<0.05) [12].
• Diabetic rats exhibited high levels of expression of PAI-1, uPA, and uPAR mRNAs and type IV collagen protein, mainly in mesangial cells [1].
• Moreover, treatment of nonmetastatic DMBA-8 cell lines with protein synthesis inhibitors led to an increase in nuclear and cytoplasmic uPA RNA levels, without altering the rate of uPA gene transcription [2].
• Urokinase plasminogen activator (uPA) has been implicated in the healing responses of injured arteries, but the importance of its various properties that influence smooth muscle cell (SMC) proliferation and migration in vivo is unclear [15].

Associations of Plau with chemical compounds

• The mRNA and activities of both urokinase-type PA (uPA) and tissue-type PA (tPA) were enhanced by PGE2 treatment [16].
• Proximal tubules freshly isolated from rats treated for 2 d with lovastatin (4 mg/kg per d) showed increased tissue-type plasminogen activator (tPA) and urokinase (uPA) activities and antigens [17].
• Proteolytically inactive r-uPA/H/Q (containing glutamine rather than histidine-204 in its catalytic site) did not affect neointima or lumen size [15].
• Using a model in which surgical partial hepatectomy is combined with feeding of 2-acetylaminofluorene (2-AAF) to induce liver regeneration by proliferation and differentiation of oval cells, expression of uPA, uPAR, and PAI-1 was detected by immunohistochemistry mainly in the duct-like formations of expanding oval cells [18].
• Following ovulation, uPA mRNA was expressed in capillary sprouts within the developing corpus luteum [19].

Regulatory relationships of Plau

• Blockade of EGFR can inhibit both cell migration and proliferation induced by uPA [20].
• TGF alpha increased basal tPA activity at both stages of follicular development but inhibited activities of uPA in undifferentiated granulosa cells, irrespective of the presence of FSH [21].
• Antibodies to uPA completely blocked the TGF-beta 1-mediated invasiveness of the RIE-Tr cells and returned their adhesiveness to basement membrane proteins to baseline [22].

Other interactions of Plau

• Immunohistochemical analyses revealed that both uPAR/uPA positive staining cells were increased in the healing tendon tissue section [12].
• Under these growth-stimulated culture conditions, tPA and uPA mRNAs were induced and up-regulated [13].
• OBJECTIVE: To assess the participation of urokinase-type (uPA) and tissue-type (tPA) plasminogen activators in embryo development and implantation [23].
• This is the first description of cross talk between uPA and EGFR in vascular smooth muscle cells [20].
• The differential activation of pathways for ERK1/2 and p38 MAPK by uPA allows for two distinct biologic responses that both require tyrosine kinase receptor transactivation [20].

Analytical, diagnostic and therapeutic context of Plau

• We used a rat Achilles tendon model to study mRNA and protein expression of uPA and its receptor (uPAR) during tendon healing using immunohistochemical, Northern and Western blot analyses [12].
• We have now documented the de novo appearance of active uPA in livers from male Fischer F344 rats that underwent 70% partial hepatectomy (PHx) as early as 1 minute after surgery [24].
• Using in situ hybridization, we detected uPA mRNA in the ovary along the route of capillary extension, originating at the existing ovarian vasculature, extending toward growing follicles, and terminating at the newly formed capillary sheaths surrounding each growing follicle [19].
• In untreated animals both tPA and urokinase-type plasminogen activator (uPA) activity was significantly increased within the region of infarct by 6 hours after reperfusion [25].
• Together, these studies demonstrate the ability of anti-uPAR antibody to decrease tumor volume and detect the presence of microscopic occult tumor metastases in malignancies where uPA/uPAR play a key role in tumor progression [26].

References