title: Overexpression of members of the AP-1 transcriptional factor family from an early stage of renal carcinogenesis and inhibition of cell growth by AP-1 gene antisense oligonucleotides in the Tsc2 gene mutant (Eker) rat model.
abstract: We previously isolated subtracted cDNA clones for genes having increased expression in Tsc2 gene mutant (Eker) rat renal carcinomas (RCs). Among them, fra-1 encoding a transcriptional factor activator protein 1 (AP-1) was identified. We have therefore investigated whether other members of the AP-1 transcription factor family might also be involved in renal carcinogenesis in the Eker rat model. In the present study, overexpression of fra-1, fra-2, c-jun, junB, and junD mRNAs was demonstrated in RCs by Northern blot analysis. Interestingly, AP-1 proteins were highly expressed even in the earliest preneoplastic lesions (e.g., phenotypically altered tubules) as suggested by immunohistochemistry. Moreover, 12-O-tetradecanoylphorbol-13-acetate-responsive element (TRE)-binding activity of AP-1 proteins was observed in RC cell extracts by electrophoretic mobility shift assay. As a next step, we transfected antisense oligonucleotides targeting AP-1 genes into RC cells and demonstrated that their growth was strongly inhibited. Thus, the data suggest that overexpression of AP-1 genes might play a crucial role in renal carcinogenesis in the Eker rat model.
authors.affiliation: Department of Experimental Pathology, Cancer Institute, 1-37-1 Kami-ikebukuro, Tokyo, Toshima-ku, 170, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Urakami
authors.forename: H
authors.initials: H
authors.lastname: Tsuchiya
authors.forename: K
authors.initials: K
authors.lastname: Orimoto
authors.forename: T
authors.initials: T
authors.lastname: Kobayashi
authors.forename: M
authors.initials: M
authors.lastname: Igawa
authors.forename: O
authors.initials: O
authors.lastname: Hino
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D051921:Fos-Related Antigen-2; D016147:Genes, Tumor Suppressor; D007668:Kidney / Q000378:metabolism; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D005810:Multigene Family; D009367:Neoplasm Staging; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D051381:Rats; D011922:Rats, Mutant Strains; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D018808:Transcription Factor AP-1 / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins
chemical_list: D004268:DNA-Binding Proteins; D051921:Fos-Related Antigen-2; C497874:Fosl2 protein, rat; D016376:Oligonucleotides, Antisense; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012097:Repressor Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins