Both increased stability and transcription contribute to the induction of the urokinase plasminogen activator receptor (uPAR) message by hypoxia.
Both hypoxia and overexpression of the urokinase plasminogen activator receptor (uPAR) are associated with a poor clinical outcome in human cancers. Hypoxia has been shown to induce uPAR expression in breast cancer cells and to increase their invasion through Matrigel, a phenomenon which can be blocked using an anti-uPAR antibody. We examined expression of uPAR mRNA in MCF7 human breast carcinoma cells under hypoxia and found that an increase in the level of the message could be detected at 1% oxygen but was most marked at 0.2 or 0.05% oxygen with an induction of 9- to 20-fold over baseline. To determine whether changes in RNA stability contributed to this dramatic increase, we used actinomycin D to inhibit transcription and found that the half-life of the message was much longer under hypoxic conditions (approximately 10 h) than during reoxygenation (approximately 2 h). Transient transfections using a luciferase reporter construct containing 2 kbp of the mouse uPAR promoter showed that promoter activity increased up to 5-fold after exposure to 0.2% oxygen. Thus, hypoxic induction of the uPAR message in MCF7 cells is due to both mRNA stabilization and increased transcriptional activation.
Maity
A
A
Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104, USA. maity@mail.med.upenn.edu
Solomon
D
D
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D004790:Enzyme Induction; D004792:Enzyme Precursors / Q000378:metabolism; D004795:Enzyme Stability / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D012333:RNA, Messenger; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D004792:Enzyme Precursors; C524898:PLAUR protein, human; C524899:Plaur protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator