Trends in Molecular Medicine
Promising molecular targets for cancer prevention: AP-1, NF-κB and Pdcd4
Section snippets
Tumor promotion and progression are problems of gene regulation
Carcinogenesis is a multistep process (Fig. 1), as was first described in 1965 by Leslie Foulds, who deduced that there were multiple, pathologically distinguishable stages in the process of cancer induction and tumor progression for many human epithelial cancers [2]. Peyton Rous, Isaac Berenblum and Roswell Boutwell pioneered the development of mouse models to study the stages of carcinogenesis [3].
Carcinogenesis can be thought of as a three-stage process. The first stage is initiation (Fig. 1
Molecular events required for tumor promotion: the mouse JB6 model is predictive
Much of the characterization of the tumor-promotion process has used animal models rather than human tissue. However, the long latent period, the chronic non-mutagenic exposures required, and the apparent reversibility in the early stages of the development of human cancers, such as cigarette-smoke-induced lung cancer, human-papillomavirus-induced cervical cancer, and Epstein–Barr-virus-induced nasopharyngeal cancer, imply that the tumor-promotion stage is also important in human carcinogenesis.
Components of AP-1, and their interactions with NF-κB, other transcription factors and inhibitor TAM67
The transcription factor AP-1 can be produced by 18 different dimeric combinations of proteins from the Jun (c-Jun, JunB and JunD) and Fos (c-Fos, FosB, Fra-1 and Fra-2) families, including Jun homodimers and Jun–Fos heterodimers (Fig. 2) 21, 22, 23, 24. The Jun and Fos proteins contain a basic-region leucine zipper (bZIP) domain, and are capable of binding to other bZIP proteins including those from the ATF, MAF, CNC and C/EBP (CCAAT/enhancer-binding protein) subfamilies [25]. Jun–Jun and
Elevated AP-1 activation is required for tumor promotion and progression
The importance of AP-1 in tumor promotion was first suggested soon after the original characterization of AP-1 (Fig. 3) [10]. By 1988 it was clear that the AP-1 proteins were Jun and Fos 23, 31, 32, 33, 34, and in 1989 a lack of responsiveness to AP-1 activation was observed in transformation-resistant JB6 cells [10]. In 1993, Brown et al. [28] created TAM67, which was then used to confirm the requirement for AP-1 in tumor promotion in JB6 cells [35] and in mouse skin [30]. Interestingly, Jnk-2
A novel tumor suppressor, Pdcd4, inhibits AP-1 transactivation and JB6 cell transformation
Pdcd4, identified by differential display of mRNA, is expressed at high levels in JB6 variants that are resistant to induced transformation. The relevance of this finding to human cancer is currently being investigated, and transgenic mice expressing Pdcd4 are being tested for possible resistance to skin tumorigenesis (A.P. Jansen and N.H. Colburn, unpublished). Expression of the Pdcd4 gene is upregulated during apoptosis 49, 50, in senescent human diploid fibroblasts [51] and in response to
Conclusions
This review has focused on validating molecular targets for cancer prevention, such as AP-1, NF-κB and Pdcd4, rather than on intervention agents that might alter their activity. However, extensive efforts have been devoted to the chemopreventive potential of pharmacological or dietary small molecules that target AP-1 or NF-κB. The use of specific retinoids in preclinical models and in the clinic has been reviewed elsewhere [54], as has the use of polyphenols, such as perillyl alcohol [55].
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