Transcriptional regulation of human survivin by early growth response (Egr)-1 transcription factor.
Survivin, a member of the inhibitor of apoptosis protein family, is involved in both, inhibition of apoptosis and regulation of cell division. Because of the tumor-specific expression of survivin, the reduction of its expression is an important therapeutic option in the treatment of malignant diseases. Thus, we analyzed the transcriptional regulation of survivin in order to establish survivin as a target gene for new therapeutic approaches. Here, we describe a novel regulatory region within the survivin promoter. After treatment with phorbol 12-myristate-13-acetate, the early growth response (Egr)-1 transcription factor binds to the sequence 5'GAGGGGGCG 3' within the human survivin promoter in vitro and in entire cells. In reporter-gene assays and overexpression experiments, survivin is downregulated following exogenous expression of wildtype Egr-1. Using p53 wildtype and mutated cell lines, we show that Egr-1 negatively regulates survivin expression and sensitizes cell lines to TRAIL-induced apoptosis.
Wagner
Mandy
M
Department of Hematology and Oncology, Universitätsmedizin Berlin, Charité, Campus Virchow, Augustenburger Platz 1, 13353 Berlin, Germany.
Schmelz
Karin
K
Dörken
Bernd
B
Tamm
Ingo
I
D017209:Apoptosis / Q000502:physiology; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004247:DNA; D051766:Early Growth Response Protein 1 / Q000378:metabolism / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology*
C107489:BIRC5 protein, human; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D004247:DNA