Tumorigenesis is a multistep process involving cell transformation, invasive growth, angiogenesis and tumor spread to distant sites (Hanahan and Weinberg, 2000). The ability of the retroviral oncogene v-Jun to transform quail embryo fibroblasts lead to the discovery of the oncogenic potential of its cellular homologue c-Jun (Bader et al., 2000; Vogt and Bos, 1989). Retroviral-mediated chronic expression of c-Jun in fibroblasts causes phenotypic changes characteristic of transformation, including sustained growth in low serum medium, ability to develop colonies in agar and to form tumors in nude mice (Castellazzi et al., 1990; Schutte et al., 1989). Cell transformation by c-Jun requires its transactivation domain, because expression of c-Jun TAM67 suppresses cancer cell growth in vitro and in nude mice and reverts the transformed phenotype of keratinocyte and mammary epithelial cells (Neyns et al, 1999; Li et al, 2000). Although c-Jun overexpression in transgenic mice does not result in the development of tumors, c-Jun ablation or its inhibition suppresses tumor progression (Grigoriadis et al, 1993). c-Jun knockout mice have drastically reduced number and size of hepatic tumors (Eferl et al, 2003). c-Jun ablation in the skin of the tumor-prone K5-SOS-F transgenic mice results in less EGF receptor expression in basal keratinocytes and smaller papillomas, and transgenic mice expressing c-Jun TAM67 in the basal keratinocytes escape chemically induced papilloma development (Zenz et al., 2003; Young et al, 1999).

Ras proteins are mutationally activated in many human cancers and are responsible for malignant transformation (Coleman et al, 2004). Compelling evidence suggests that c-Jun expression and activity are required for Ras-induced cell transformation, because c-Jun-null fibroblasts are resistant to Ras-induced transformation and c-Jun 63/73 AA transgenic mice are impaired in skin tumor development induced by expressing of SOS K5-SOS-F that activates the Ras pathway (Schutte et al, 1989; Johnson et al, 1996; Behrens et al, 2000). Since the constitutively active Ras activates MAPKs that lead to c-Jun phosphorylation, it is possible that c-Jun is an essential downstream mediator for Ras to induce cell transformation (Sistonen et al, 1989; Pertovaara etal, 1989; Mansour et al, 1994).

In transformed cells, c-Jun is expressed constitutively at high levels, which may contribute to tumor progression (Carter et al, 1994; Piette et al, 1988). High c-Jun expression possibly co-operates with tumor specific proteins, such as the prolyl isomerase Pinl, which is distinctly overexpressed in breast cancer cells. Pinl binds to the N-terminal phosphorylated c-Jun to activate the cyclin D1 promoter, thereby promoting tumor cell growth (Wulf et al, 2001). Conversely, the tumor suppressors Pdcd4 and JDP2 bind to and inactivate c-Jun to suppress the constitutive AP-1 activity in tumor cells and to inhibit tumor phenotype (Yang et al, 2003; Heinrich et al, 2004).

cDNA microarray studies have been employed to search for c-Jun-regulated genes involved in cell transformation and tumorigenesis. Differential gene expression profiles have been established by comparing mRNAs from TPA-treated epidermal cells that are either transformed by wild type c-Jun or by non-transformed c-Jun TAM-67. The high-mobility group protein Al (HMGA1) has been identified as a TPA-induced and c-Jun transactivation domain dependent protein. HMGA1 expression is essential for epidermal cell transformation; however, its expression alone is insufficient, suggesting that c-Jun must control the expression of a group of genes for a combined effect on the transformation phenotype (Dhar et al, 2004). In transformed tumor cells, profiling the AP-1 target genes has revealed tumor suppressor TSCL-1 and gelsolin-like actin capping protein CapG, demonstrating a role for AP-1 in tumor cell motility and cytoskeletal dynamics (Bahassi et al, 2004). The apparent differences in gene expression profile revealed by these studies support the idea that c-Jun regulated gene expression is cell type and cell transformation status dependent. Finding the c-Jun target genes responsible for cell transformation and tumor promotion will uncover pertinent targets for cancer prevention. In this regard, this is area will be worthwhile of more extensive investigation.

Concluding Remarks

After close to two decades of extensive efforts, we have become painfully aware of the complex nature of c-Jun regulation and function. Still, as originally believed, c-Jun is a transcription factor that binds to a relatively simple sequence in the regulatory domain of genes, but just its ability to bind DNA and activate AP-1-driven promoters is insufficient to explain its role in diverse and sometimes opposing physiological processes, including proliferation, apoptosis, survival, tumorigenesis and tissue morphogenesis. c-Jun-mediated cell responses can be affected by many factors and are dependent on the abundance of c-Jun protein, its dimerization partners, and its interactions with other transcription factors, co-activators and co-repressors. All these parameters may be influenced by subtle alterations of the signaling properties within a cell that modulate c-Jun or its co-factors. There are still too many unknowns involved in c-Jun regulation and function. For instance, we do not know how various signals cross-talk in the regulation of c-Jun activities and how c-Jun selects its target genes in a tissue or cell type specific manner. In this regard, genetic knockout mice or cells that are deficient in c-Jun regulation pathways are instrumental in elucidating the signaling and genetic programs controlled by c-Jun.


The author would like to thank Dr. Alvaro Puga for proof reading of this article.

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook

Post a comment