Regulation of transforming growth factor-beta 1 (TGF-beta 1) expression with a novel TGF-beta 1 complementary DNA.
We describe here a novel TGF-beta 1 complementary DNA (antisense oligomer) that is specific for TGF-beta 1 genomic DNA. The TGF-beta 1 antisense oligomer, complementary to the nucleotides flanking the first transcription start site of the human TGF-beta 1 gene and phosphorothioate modified, was efficacious in: a) constraining TGF-beta 1 promoter activity; b) reducing TGF-beta 1 secretion; and c) preventing TGF-beta 1 dependent inhibition of DNA synthesis in TGF-beta sensitive A-549 human adenocarcinoma cells. The biologic activities of the TGF-beta 1 antisense oligomer were sequence specific since neither the TGF-beta 1 sense oligomer nor the TGF-beta 1 missense oligomer prevented TGF-beta 1 expression. Our findings, in addition to demonstrating the efficacy and specificity of the TGF-beta 1 antisense oligomer, suggest that the oligomer might be of value for the treatment of diseases in which TGF-beta 1 overexpression might play a pathogenetic role (e.g., diabetic renal disease, AIDS).
Khanna
A
A
Rogosin Institute, Department of Transplantation Medicine and Extracorporeal Therapy, New York, New York.
Li
B
B
Li
P
P
Suthanthiran
M
M
D000230:Adenocarcinoma; D001483:Base Sequence; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D004261:DNA Replication / Q000187:drug effects*; D018076:DNA, Complementary; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D063086:Organothiophosphates; D011401:Promoter Regions, Genetic / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured
D018076:DNA, Complementary; D016376:Oligonucleotides, Antisense; D063086:Organothiophosphates; D016212:Transforming Growth Factor beta; D016572:Cyclosporine