Role of distinct mitogen-activated protein kinase pathways and cooperation between Ets-2, ATF-2, and Jun family members in human urokinase-type plasminogen activator gene induction by interleukin-1 and tetradecanoyl phorbol acetate.
We have investigated the in vivo and in vitro regulation of the human urokinase-type plasminogen activator (uPA) gene by interleukin-1 (IL-1) and analyzed the transcription factors and signalling pathways involved in the response of the -2.0-kb uPA enhancer to IL-1 induction and to tetradecanoyl phorbol acetate (TPA) induction. Mutational analysis showed the cooperative activity of the Ets-binding site (EBS) and the two AP-1 elements of the enhancer. The results reveal that the EBS is required for the response to both inducers mediated by Ets-2, which is regulated at a level subsequent to DNA binding, by an IL-1- and phorbol ester-inducible transactivation domain. Both the IL-1 and the TPA-mediated induction result in a drastic increase of AP-1 binding to the downstream site of the enhancer (uPA 3' TPA-responsive element), while a mostly qualitative change, resulting from the interplay between ATF-2 homodimers and c-Jun-ATF-2 heterodimers, takes place at the upstream AP-1 element. The analysis of two distinct mitogen-activated protein kinase pathways shows that stress-activated protein kinase-Jun N-terminal kinase activation, resulting in the phosphorylation of ATF-2, c-Jun, and JunD, is required not only for the IL-1- but also for the TPA-dependent induction, while the extracellular signal-related kinase 1 (ERK-1) and ERK-2 activation is involved in the TPA- but not in the IL-1-dependent stimulation of the uPA enhancer.
Cirillo
G
G
International Institute of Genetics and Biophysics, CNR, 80125 Naples, Italy.
Casalino
L
L
Vallone
D
D
Caracciolo
A
A
De Cesare
D
D
Verde
P
P
D051698:Activating Transcription Factor 2; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004247:DNA / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D008969:Molecular Sequence Data; D050787:Proto-Oncogene Protein c-ets-2; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics*
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D017931:DNA Primers; D004268:DNA-Binding Proteins; C107465:ERF protein, human; C494069:ETS2 protein, human; D007375:Interleukin-1; D050787:Proto-Oncogene Protein c-ets-2; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D012097:Repressor Proteins; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D004247:DNA; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D014568:Urokinase-Type Plasminogen Activator; D013755:Tetradecanoylphorbol Acetate