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Radiation and Transforming Growth Factor-ß Cooperate in Transcriptional Activation of the Profibrotic Plasminogen Activator Inhibitor-1 Gene

Authors' Affiliations: Departments of ¹ Radiation and Stress Cell Biology and ² Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; ³ Department of Developmental Genetics, Biological Center, Haren, the Netherlands

Requests for reprints: Robert P. Coppes, Department of Radiation and Stress Cell Biology, University Medical Center Groningen, University of Groningen, 5th Floor, Building 3215, Ant. Deusinglaan 1, 9713 AV Groningen, the Netherlands. Phone: 31-50-3632709; Fax: 31-50-3632913; E-mail: r.p.coppes{at}med.umcg.nl.

Radiation-induced fibrosis is an important side effect in the treatment of cancer. Profibrotic proteins, such as plasminogen activator inhibitor-1 (PAI-1), transforming growth factor-ß (TGF-ß), and tissue type inhibitor of metalloproteinases-1 (Timp-1), are thought to play major roles in the development of fibrosis via the modulation of extracellular matrix integrity. We did a detailed analysis of transcriptional activation of these profibrotic genes by radiation and TGF-ß. Irradiation of HepG2 cells led to a high increase in PAI-1 mRNA levels and a mild increase in Timp-1 mRNA levels. In contrast, TGF-ß1 and Smad7 were not increased. Radiation and TGF-ß showed strong cooperative effects in transcription of the PAI-1 gene. The TGF-ß1 gene showed a mild cooperative activation, whereas Timp-1 and Smad7 were not cooperatively activated by radiation and TGF-ß. Analysis using the proximal 800 bp of the human PAI-1 promoter revealed a dose-dependent increase of PAI-1 levels between 2 and 32 Gy -rays that was independent of latent TGF-ß activation. Subsequent site-directed mutagenesis of the PAI-1 promoter revealed that mutation of a p53-binding element abolished radiation-induced PAI-1 transcription. In line with this, PAI-1 was not activated in p53-null Hep3B cells, indicating that p53 underlies the radiation-induced PAI-1 activation and the cooperativity with the TGF-ß/Smad pathway. Together, these data show that radiation and TGF-ß activate PAI-1 via partially nonoverlapping signaling cascades that in concert synergize on PAI-1 transcription. This may play a role in patient-to-patient variations in susceptibility toward fibrosis after radiotherapy.

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