Carcinogenesis and transcriptional regulation through Maf recognition elements

Abstract

Many studies on carcinogenesis carried out early in the last century are united on the consensus that cancer is a genetic disease. Cancer cells typically display gene dysfunction and endogenous or exogenous insults resulting in gene dysfunction are often carcinogenic. Recent advances in stem cell biology added the new concept that cancer originates from a single cancer-initiating cell. To understand the molecular basis of carcinogenesis from the beginning to the full acquirement of malignancy, factors concerned with carcinogenesis were categorized into three groups: those guarding and stabilizing genomes, those regulating cell proliferation, and those conferring resistance to various micro-environmental stresses. One example of particular interest is the Keap1-Nrf2 system since, according to recent studies, it has turned out to be ambivalent. Nrf2 heterodimerizes with small Maf protein to strongly activate transcription through the Maf recognition element (MARE) and Keap1 is an inhibitory regulator of Nrf2. The genes regulated by Nrf2 are very important for cellular protection of the genome from xenobiotic and oxidative stresses and, consequently, for preventing carcinogenesis. This implies that enhancing Nrf2 activity is a promising method for thwarting cancer. On the contrary, the constitutive activation of Nrf2 due to mutations in the keap1 gene is characteristically observed in lung cancer cells, suggesting that induced expression of Nrf2 target genes favors the prevalence of cancer cells.

Figure 1

The distinct contribution of Maf‐containing dimers (Nrf2‐small Maf heterodimer and large Maf homodimer) to carcinogenesis through binding to the MARE and its related sequences. The Nrf2‐small Maf heterodimer activates transcription of detoxification enzyme genes and antioxidant responsive genes. Cyclin D2 and integrin β7 are candidate target genes of c‐Maf, one of the large Maf proteins. The Nrf2‐small Maf heterodimer tends to require a conserved core region (shown in green) of the MARE, while the large Maf homodimer prefers to bind to the site where a flanking region (shown in blue) is conserved.

Figure 2

The Keap1‐Nrf2 system under quiescent and stimulated conditions. Stabilized Nrf2 is translocated into nuclei and activates transcription. The Nrf2 target genes encode critical effectors for cancer prevention, which at the same time are effective regulators of cancer cell survival.