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.
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.
Urakami
S
S
Department of Experimental Pathology, Cancer Institute, 1-37-1 Kami-ikebukuro, Tokyo, Toshima-ku, 170, Japan.
Tsuchiya
H
H
Orimoto
K
K
Kobayashi
T
T
Igawa
M
M
Hino
O
O
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
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