Dominant-negative activator protein 1 (TAM67) targets cyclooxygenase-2 and osteopontin under conditions in which it specifically inhibits tumorigenesis.
Activation of activator protein 1 (AP-1) and nuclear factor kappaB (NFkappaB)-dependent transcription is required for tumor promotion in cell culture models and transgenic mice. Dominant-negative c-Jun (TAM67) blocks AP-1 activation by dimerizing with Jun or Fos family proteins and blocks NFkappaB activation by interacting with NFkappaB p65. Two-stage [7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)] skin carcinogenesis experiments in a model relevant to human cancer risk, transgenic mice expressing human papillomavirus 16 E7 oncogene (K14-HPV16-E7), show E7-enhanced tumor promotion. A cross to K14-TAM67-expressing mice results in dramatic inhibition of tumor promoter-induced AP-1 luciferase reporter activation and papillomagenesis. Epithelial specific TAM67 expression inhibits tumorigenesis without affecting TPA- or E7-induced hyperproliferation of the skin. Thus, the mouse model enriches for TAM67 targets relevant to tumorigenesis rather than to general cell proliferation or hyperplasia, implicating a subset of AP-1- and/or NFkappaB-dependent genes. The aim of the present study was to identify target genes responsible for TAM67 inhibition of DMBA-TPA-induced tumorigenesis. Microarray expression analysis of epidermal tissues revealed small sets of genes in which expression is both up-regulated by tumor promoter and down-regulated by TAM67. Among these, cyclooxygenase-2 (Cox-2/Ptgs2) and osteopontin (Opn/Spp1) are known to be functionally significant in driving carcinogenesis. Results identify both Cox-2 and Opn as transcriptional targets of TAM67 with CRE, but not NFkappaB sites important in the Cox-2 promoter and an AP-1 site important in the Opn promoter.
Matthews
Connie P
CP
Laboratory of Cancer Prevention, National Cancer Institute, Frederick, Maryland 21702, USA. cmatthews@mail.ncifcrf.gov
Birkholz
Alysia M
AM
Baker
Alyson R
AR
Perella
Christine M
CM
Beck
George R
GR
Young
Matthew R
MR
Colburn
Nancy H
NH
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000235:genetics; D053495:Osteopontin / Q000096:biosynthesis / Q000235:genetics*; D050725:Papillomavirus E7 Proteins; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000235:genetics*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics*; D013755:Tetradecanoylphorbol Acetate; D018808:Transcription Factor AP-1 / Q000235:genetics*; D014158:Transcription, Genetic; D014162:Transfection
D022762:CCAAT-Enhancer-Binding Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D016328:NF-kappa B; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D010446:Peptide Fragments; D016755:Proto-Oncogene Proteins c-jun; C439528:TAM67 peptide; D018808:Transcription Factor AP-1; C059731:oncogene protein E7, Human papillomavirus type 16; D053495:Osteopontin; D015127:9,10-Dimethyl-1,2-benzanthracene; D051546:Cyclooxygenase 2; D013755:Tetradecanoylphorbol Acetate