1. Date of download: 7/10/2016 Copyright © 2016 McGraw-Hill Education. All rights reserved. Basic steps of gene expression—transcription factors regulate transcription, whereas microRNAs regulate (repress) translation. In the process of gene expression, information from a gene is used in the synthesis of a functional gene product. This simplified figure depicts how the synthesis of two important functional gene products, that is, proteins and microRNAs (miRNA, also called small silencing RNA), are interrelated. As described in the text, these normally controlled processes may be dysregulated by endobiotics and xenobiotics as well as during pathologic processes, such as carcinogenesis. Genetic information in a protein-coding gene (red in the DNA strand) is transcribed into a precursor messenger RNA (mRNA), which is processed into the mature mRNA by capping at the 5′ end, splicing (ie, removing noncoding introns) and polyadenylation at the 3′ end (not shown). After export from the nucleus, the mRNA associates with the ribosome and serves as a template to determine the amino acid (aa) sequence of the protein being synthesized (translation). DNA sequences between protein-coding genes (ie, intergenic regions) may code for miRNAs. These are small noncoding RNA molecules (21–25 nucleotides in length) that may control the translation of more than 60% of mRNAs into proteins. The gene for miRNA (black in the DNA strand) codes for an initial transcript, termed pri-miRNA, which may be several kilobases long (not shown; Wahid et al., 2010). The pri-miRNA is then cut shorter in the nucleus by an RNase (Drosha), assisted by its partner protein DiGeorge syndrome critical region in gene 8 (DGCR8), to become pre-miRNA (60–70 nucleotides in length). After export into the cytoplasm, the pre-miRNA is further truncated by another RNase (Dicer) and its partner TRBP to form the mature miRNA. Finally, miRNA associates with an Argonaute protein, thus forming microRNA-induced silencing complex (miRISC). The miRNA guides miRISC to specifically recognize mRNAs, called target mRNAs. The miRNA binds with base pairing to the untranslated region (UTR) of the target mRNA and miRISC downregulates its translation into protein by translational repression and/or mRNA cleavage. Because miRNAs bind to their target mRNAs by partial complementarity over a short sequence, one miRNA may have several hundreds of mRNA targets; therefore, a single miRNA can silence the expression of many proteins. Often a single pri-miRNA is processed into a cluster of miRNAs; therefore, their expression pattern is usually similar. A well-known example is the miR17-92 cluster comprising 7 miRNAs that are often overexpressed in cancer. Ligand- and signal-activated transcription factors (represented by the round and the rectangular symbols, respectively) can bind to the promoter regions (green in the DNA strand) of the protein-coding genes and the miRNA-coding genes and upregulate or downregulate their transcription, thereby directly influencing the expression of mRNA and/or miRNA and ultimately affecting the synthesis of specific proteins. Transcription factors and miRNAs thus regulate diverse cellular pathways. It is important to note that miRNAs, as a rule, repress the translation of proteins. Therefore, upregulation of miRNA transcription results in downregulation of protein translation from the target mRNAs, whereas downregulation of miRNA causes derepression of protein translation from the target mRNAs, thereby increasing the synthesis of specific proteins. 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