Roles of MicroRNA in T-Cell Leukemia

Previously, cancer researchers have been focused on the genes that code proteins. They have considered those effects on tumorigenesis. However, discoveries of microRNAs (miRNAs) have shed a light on the role of non-protein-coding RNAs in tumorigenesis. The first small non-coding RNA, named lin-4 in Caenorhabditis elegans (C. elegans) was described by Lee et al in 1993 (Lee et al., 1993). Lin-4 codes miRNA that regulates the timing of C. elegans larval development by translational repression (Ambros, 2000). Since then, many miRNAs in different organisms such as plants, C. elegans, Drosophila, and mammals including humans have been discovered substantially. Up to now, the human genome is predicted to encode as many as 1,000 miRNAs. miRNAs belong to a class of regulatory genes that are single-stranded 19-25 nucleotides non-cording RNAs and are generated from endogenous hairpin-shaped transcripts (Kim, 2005). miRNA genes are located either within the introns or exons of protein-coding genes (70%) or in intergenic regions (30%). More than 50% of mammalian miRNAs are located within the intronic regions of protein-coding genes. Most of the intronic or exonic miRNAs are transcribed in parallel with their host genes, indicating that these miRNAs use their host genes transcriptional machinalies. On the other hand, miRNAs produced from intergenic regions are transcribed separately from internal promoters (Rodriguez et al., 2004). The first step of miRNA synthesis is the transcription of primary miRNA (pri-miRNA) from miRNA genes (Fig.1). pri-miRNAs are transcribed in a RNA polymerase II (Pol II) dependent manner as several hundreds or thousands of nucleotides long polyadenylated RNAs. In the nucleus, the pri-miRNA is processed to a precursor miRNA (pre-miRNA) of 60-100 nucleotides in length with a stem-loop structure by the nuclear protein Drosha that belongs to class II RNase III. Drosha interacts with its cofactor DGCR8 (the DiGeorge syndrome critical region gene 8 protein). Then, the pre-miRNA is exported from the nucleus to the cytoplasm by the Exportin 5/Ran-GTP complex. In the cytoplasm, the pre-miRNA is cleaved by class III RNase III, Dicer, which is a 200-kDa protein and miRNA is produced. Primary function of miRNAs in the cytoplasm is the negative regulation of gene expression by binding to complementary target sequences in the 3' untranslated region (UTR) of mRNA. Binding of a miRNA to the target mRNA typically leads to translational repression or degradation of mRNA, which means that miRNAs repress the expression of the target genes. In mammals, miRNAs guide the RNA induced silencing complex (RISC) to