Ets up-regulates MET transcription.
MET, a potentially harmful oncogene controlling invasive growth, is overexpressed in a significant percentage of human cancers. Since amplification of the MET gene occurs only in a fraction of these cases, we investigated the transcriptional mechanisms responsible for up-regulation of the promoter activity. The transcription driven by the 3.1 kbp DNA fragment containing the minimal promoter was studied by 5' progressive deletion analysis. The patterns of MET promoter activity suggest the presence of weak negative and positive elements in the region between 300 and 840 bp upstream to the transcription start site. The region encompassing the first 300 bp strongly up-regulates the promoter. This region contains four putative binding sites for members of the Ets transcription factor family, known to be involved in invasive growth. Transient co-expression of Ets1 resulted in a strong enhancement of the MET promoter activity. Increased expression of the Met protein was observed in cells stably transfected with ETS1. Double stranded oligonucleotides with Ets consensus sequence were used as a 'decoy' to inhibit binding to DNA native sites. They dramatically reduced the amount of Met protein in a human carcinoma cell line overexpressing the oncogene. Interestingly, Met activation induces transcription of ETS1 mRNA, showing that Ets proteins act both upstream and downstream to MET. These data indicate that members of the Ets family promote MET transcription and suggest their contribution to the invasive phenotype through overexpression of MET.
Gambarotta
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G
Institute for Cancer Research, University of Torino Medical School, Italy.
Boccaccio
C
C
Giordano
S
S
Andŏ
M
M
Stella
M C
MC
Comoglio
P M
PM
D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D015854:Up-Regulation
D004268:DNA-Binding Proteins; C494041:ETS1 protein, human; C494042:Ets1 protein, mouse; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases