deSilva, Leel; (1994) The regulation of tissue plasminogen activator in rat brain glioma cells. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Plasminogen activators have been implicated in physiological events including fibrinolysis and tissue remodelling, and in invasion and metastasis by neoplastic cells. Previous work has shown higher tissue plasminogen activator (tPA) activity in the ethylnitrosourea induced glioma line A15A5 compared with the clone from normal tissue, ARBO C9. The difference in mRNA was 10 to 20 fold while that in activity was greater, usually 50 to 80 times. The present work was directed towards finding out what mechanisms could account for these differences and for the effects of extrinsic factors on tPA activity of A15A5. cDNA clones (approximately 1700 bases) for both lines which included the entire 3' untranslated region were sequenced. No differences were found. Both have putative AU-rich stability elements. Nuclear run-ons showed only about a 2-fold higher rate of transcription for A15A5. The transcript of A15A5 most of which is in the nucleus, shows little decay over 6 hours in the presence of actinomycin D. The level of ARBO C9 mRNA is too low to measure decay. Many extrinsic factors affect plasminogen activator (PA) activity. These include the tissue protein plasminogen activator inhibitor-1 (PAI-1), as well as hormones and growth factors. Previous work has shown that cholera toxin (CT) increases and dexamethasone (Dex) decreases PA activity in A15A5. Present results suggest that CT primarily affect transcription of the tPA gene while the effect of Dex on PA activity is mediated through PAI-1. The results show that post-transcriptional events are important in maintaining a high level of tPA transcripts in A15A5. The presence of most of the message in the nucleus and the lack of transcript in ARBO C9 despite a comparable transcription rate suggest regulation of stability in the nucleus.

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