1. Date of download: 6/23/2016 Copyright © 2016 McGraw-Hill Education. All rights reserved. A model depicting the modes of action of genotoxic and nongenotoxic carcinogens and the cooperation between proto-oncogenes and tumor suppressor genes in transformation of normal cells with controlled proliferation into neoplastic cells with uncontrolled proliferation. When produced in appropriate quantities, the normal proteins encoded by proto-oncogenes [1] and tumor suppressor genes [2] reciprocally influence mitosis and apoptosis and thus ensure controlled cell proliferation. However, the balance between the effects of these 2 types of proteins on the fate of cells is offset by carcinogens via genotoxic and nongenotoxic mechanisms resulting in uncontrolled proliferation. A genotoxic (or DNA-reactive) carcinogen may induce cell proliferation in 2 ways. In the first way, it inflicts DNA damage (eg, by forming DNA adducts) that ultimately brings about an activating mutation [3] in a proto-oncogene [1] and the mutant proto-oncogene (then called an oncogene) [4] in turn encodes a constitutively (ie, permanently) active oncogene protein [5] that continuously signals for mitosis or against apoptosis [6], depending on its function. In the second way, the DNA-reactive chemical produces DNA damage that eventually yields an inactivating mutation [7] in a tumor suppressor gene [2], with the mutant gene [8] encoding an inactive tumor suppressor protein [9] that cannot restrain mitosis or evoke apoptosis (eg, in response to DNA damage). In both instances, the rate of mitosis will exceed the rate of apoptosis [6] and uncontrolled proliferation of the affected cells will ensue [10]. Such a scenario may underlie the carcinogenicity of aflatoxin B 1, which induces mutation sometimes in the Ras proto-oncogene and often in the p53 tumor suppressor gene (see text for details). Nongenotoxic (epigenetic) carcinogens may also induce cell proliferation by 2 modes of action: first, by causing the overexpression of normal proto-oncogenes [1], yielding increased quantity of their protein products [11], which in turn excessively stimulate mitosis or inhibit apoptosis [12]. The second mode involves the underexpression of normal tumor suppressor genes [2], yielding diminished quantity of their protein products [13], which thus fail to restrain mitosis or promote apoptosis appropriately [12]. Nongenotoxic carcinogens may induce the synthesis of proto-oncogene proteins [11] at transcriptional and/or translational levels. They may facilitate the transcription of a proto-oncogene [1] into its mRNA [14] either by increasing the abundance of active transcription factors (TFs) at the promoter region of the gene or by facilitating the accessibility of TFs to the promoter (eg, by hypomethylation of this region) [15]. Nongenotoxic carcinogens may promote the translation of the mRNA into proto-oncogene protein [16] by decreasing the expression of microRNA (miRNA) [17] that normally represses the translation of this protein [16]. (Such miRNAs have tumor suppressor roles.) Nongenotoxic (also called epigenetic) carcinogens also may reduce the synthesis of tumor suppressor proteins [13] at transcriptional and/or translational levels. They may diminish the transcription of a tumor suppressor gene [2] into its mRNA [18] either by decreasing the abundance of active TFs at the promoter region of the gene or by impeding the accessibility of TFs to the promoter (eg, by hypermethylation of this region) [19]. Nongenotoxic carcinogens may downregulate the translation of the mRNA into a tumor suppressor protein [20] by increasing the expression of a miRNA [21] that normally represses the translation of this protein [20]. (Such miRNAs have oncogenic roles.) Eventually, overexpression of proto-oncogene proteins and/or underexpression of tumor suppressor proteins produce mitosis rate that exceeds the rate of apoptosis [12], thereby leading to uncontrolled proliferation of the affected cells [22]. Examples for nongenotoxic carcinogens acting by these mechanisms are given in the text. In effect, the modes of action of these 2 types of chemical carcinogens are more complex: genotoxic carcinogens may also exert epigenetic effects and nongenotoxic carcinogens may increase the frequency of spontaneous mutations as well as the division and survival of cells carrying mutations (see the text for details). Legend : From: Mechanisms of Toxicity Casarett and Doull's Toxicology: The Basic Science of Poisons, 8e, 2012 From: Mechanisms of Toxicity Casarett and Doull's Toxicology: The Basic Science of Poisons, 8e, 2012