Meta-Biol

• Pathways

Localization of FOXO transcription factors FOXO1, FOXO3 and FOXO4 is regulated by AKT-mediated phosphorylation. In the absence of PI3K/AKT signaling, FOXO1, FOXO3 and FOXO4 localize to the nucleus. AKT-mediated phosphorylation induces a conformational change that exposes a nuclear export signal (NES) and promotes translocation of FOXO1, FOXO3 and FOXO4 to the cytosol (Rena et al. 1999, Brunet et al. 1999, Kops et al. 1999). AKT-phosphorylated FOXO1, FOXO3 and FOXO4 bind to 14-3-3 proteins, which contributes to their retention in the cytosol (Rena et al. 2001, Brunet et al. 1999, Arimoto Ishida et al. 2004, Obsilova et al. 2005, Boura et al. 2007, Silhan et al. 2009). FOXO6 lacks the NES sequence and is exclusively nuclear, but phosphorylation in response to PI3K/AKT signaling affects the transcriptional activity of FOXO6 (Jacobs et al. 2003, van der Heide et al. 2005).

RNA polymerase II (Pol II) is the central enzyme that catalyses DNA- directed mRNA synthesis during the transcription of protein-coding genes. Pol II consists of a 10-subunit catalytic core, which alone is capable of elongating the RNA transcript, and a complex of two subunits, Rpb4/7, that is required for transcription initiation.
The transcription cycle is divided in three major phases: initiation, elongation, and termination. Transcription initiation include promoter DNA binding, DNA melting, and initial synthesis of short RNA transcripts. The transition from initiation to elongation, is referred to as promoter escape and leads to a stable elongation complex that is characterized by an open DNA region or transcription bubble. The bubble contains the DNA-RNA hybrid, a heteroduplex of eight to nine base pairs. The growing 3-end of the RNA is engaged with the polymerase complex active site. Ultimately transcription terminates and Pol II dissocitates from the template.

Gene expression encompasses transcription and translation and the regulation of these processes. RNA Polymerase I Transcription produces the large preribosomal RNA transcript (45S pre-rRNA) that is processed to yield 18S rRNA, 28S rRNA, and 5.8S rRNA, accounting for about half the RNA in a cell. RNA Polymerase II transcription produces messenger RNAs (mRNA) as well as a subset of non-coding RNAs including many small nucleolar RNAs (snRNA) and microRNAs (miRNA). RNA Polymerase III Transcription produces transfer RNAs (tRNA), 5S RNA, 7SL RNA, and U6 snRNA. Transcription from mitochondrial promoters is performed by the mitochondrial RNA polymerase, POLRMT, to yield long transcripts from each DNA strand that are processed to yield 12S rRNA, 16S rRNA, tRNAs, and a few RNAs encoding components of the electron transport chain. Regulation of gene expression can be divided into epigenetic regulation, transcriptional regulation, and post-transcription regulation (comprising translational efficiency and RNA stability). Epigenetic regulation of gene expression is the result of heritable chemical modifications to DNA and DNA-binding proteins such as histones. Epigenetic changes result in altered chromatin complexes that influence transcription. Gene Silencing by RNA mostly occurs post-transcriptionally but can also affect transcription. Small RNAs originating from the genome (miRNAs) or from exogenous RNA (siRNAs) are processed and transferred to the RNA-induced silencing complex (RISC), which interacts with complementary RNA to cause cleavage, translational inhibition, or transcriptional inhibition.