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Oncogene. 2001 Apr 5;20(15):1816-24.

The small-GTPase RalA activates transcription of the urokinase plasminogen activator receptor (uPAR) gene via an AP1-dependent mechanism.

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  • 1School of Biomedical Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK.

Abstract

The urokinase plasminogen activator receptor (uPAR) focuses extracellular protease activity to the cell surface, modulates cell adhesion and activates intracellular signal transduction pathways. In a range of cancers uPAR expression often has a negative correlation with prognosis. Here we show that uPAR transcription is stimulated by V12 H-Ras, the effector loop mutant V12 H-Ras G37 and constitutively-active RalA 72L. RalA-dependent transcription required the presence of the ATF2-like AP1-site at -70 bp and the c-Jun binding motif at -184 bp in the uPAR promoter. Consistent with this, both Gal4-c-Jun- and Gal4-ATF2-fusion proteins were activated by RalA signalling through phosphorylation of their activation domains at Ser63 and Ser73 of c-Jun or Thr69 and Thr71 of ATF2. A transdominant inhibitory mutant of c-Jun N-terminal kinase (JNK) failed to inhibit uPAR transcription demonstrating that JNK activation is not a prerequisite for RalA-dependent uPAR transcription. A dominant negative inhibitor of c-Src effectively inhibited RalA-dependent uPAR transcription identifying it as a downstream effector in the RalA signalling pathway. These data provide evidence for the existence of a novel signalling pathway that links RalA to the activation of uPAR transcription via a c-Src intermediate and activation of AP1.

PMID:
11313929
[PubMed - indexed for MEDLINE]
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