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Signal transduction and exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Brendan Egan, Adam P. Sharples
The primary transcript produced by RNA polymerase II undergoes post-transcriptional processing to become mRNA that can be translated into protein. Most human genes consist of multiple exons, which is the part of the gene that encodes the protein interspersed by introns or intervening sequences. Introns are removed by spliceosomes and, depending on which exons are retained, different splice variants of the gene can be created. A well-known example relevant to exercise physiology is the alternative splicing of the IGF-I gene to create mechano-growth factor (MGF, also referred to as IGF-IEc in humans or IGF-IEb in rodents), which was discovered by Geoffrey Goldspink’s group in the late 1990s (62). The activity of spliceosomes is in part regulated by proteins that recognise and mark different splice sites, but as yet it is unclear as to how exercise regulates alternative splicing.
Acute and Chronic Transforming Retroviruses
Published in Pimentel Enrique, Oncogenes, 2020
In general, there exists a correlation between LTR transcriptional activity, LTR-induced enhancement of messenger RNA transcription, and retroviral oncogenic potential.162 This phenomenon is probably related to the presence within LTR of particular sequences termed activator or enhancer sequences. The promoter and the enhancer are interacting but functionally distinct elements that form parts of the transcriptional control regions of genes transcribed by RNA polymerase II.163 At least some promoters are inactive in the absence of an enhancer element. According to a model, the LTR enhancer of RSV is located entirely within the LTR U3 region and 5′ to the promoter of the same region.164 Enhancer sequences have been associated with DNA tumor viruses (SV40, BKV, PV, adenovirus) and are also present in the eukaryotic genome. These sequences are able to enhance gene expression by an as yet undefined mechanism but they are less restricted by position than classical promoters and play an important role in regulation of gene expression. In contrast to promoter elements, the enhancers may act in any orientation and at a distance from the gene whose expression is being modulated.
SBA Answers and Explanations
Published in Vivian A. Elwell, Jonathan M. Fishman, Rajat Chowdhury, SBAs for the MRCS Part A, 2018
Vivian A. Elwell, Jonathan M. Fishman, Rajat Chowdhury
In prokaryotes, both transcription and translation occur in the cytoplasm; whereas in eukaryotes, transcription occurs in the nucleus and translation in the cytoplasm. Transcription is the process of synthesizing messenger RNA (mRNA) from DNA; it is catalysed by the enzyme RNA polymerase II. RNA and DNA are always synthesized in a 5ʹ → 3ʹ direction.
Molecular mechanisms of ferroptosis and their role in inflammation
Published in International Reviews of Immunology, 2023
Feng Wang, Jingya He, Ruxiao Xing, Tong Sha, Bin Sun
There is no clearly defined pathogenesis of ferroptosis; however, iron overload and the concomitantly occurring lipid peroxidation and inflammation are the three distinguishing signs of ferroptosis. The accumulation of iron caused by abnormal metabolism is considered a factor in aggravation of inflammation [18]. One of the latest discoveries pertaining to nuclear factor erythroid 2-related factor 2 (Nrf2) downstream signal transduction is the resistance to ferroptosis. Nrf2 resists ferroptosis by coordinating iron/metal metabolism, intermediate metabolism, and GSH synthesis/metabolism [19]. Nrf2 activates several downstream metabolic pathways that regulate reduction of free iron, inhibition of lipid peroxidation, and elevation in GSH. levels. Another important cellular protective mechanism of Nrf2 acts via the anti-inflammatory pathway. In addition to breaking the vicious circle of inflammation and local ROS accumulation through redox regulation, Nrf2 inhibits nuclear factor-κB (NF-κB) transcription [20]. NF-κB and Nrf2 have complex associations with each other. There are several effective NF-κB binding sites in the promoter region of Nrf2 [21]. Nrf2 and IκB kinase share an identical degradation mechanism, which is mediated by Keap1 [22]. Nrf2 and NF-κB compete for the binding site of p300 [23]. Binding to its extension region prevents the recruitment of RNA polymerase II. Nrf2 also inhibits the pro-inflammatory genes encoding IL-6 and IL-1b [24].
Folic acid: a potential inhibitor against SARS-CoV-2 nucleocapsid protein
Published in Pharmaceutical Biology, 2022
Yu-meng Chen, Jin-lai Wei, Rui-si Qin, Jin-ping Hou, Guang-chao Zang, Guang-yuan Zhang, Ting-ting Chen
The study identified the pivotal genes and effective compounds through analysis of effective compounds and drug targets of COVID-19 in clinical TCM and CWM. In total, 8355 drug targets were found; these were involved in positive regulation of transcription via RNA polymerase II promoter, nucleus, and protein-binding categories, all associated with the cancer pathway. DEGs from the GEO database and drug targets were correlated, and 113 targets related to SARS-CoV-2 were found. The related targets were involved in the type I interferon signalling pathway, defense response to virus, cytoplasm, cytosol, protein binding, and herpes simplex infection. Folic acid was found to act on SARS-CoV-2 N by molecular docking. The cell experiment showed that folic acid antagonises the inhibitory effect of SARS-CoV-2 N protein on the RNA interference pathway. This study promoted the underlying interaction mechanism between the virus and host, expanded the medicinal scope of folic acid, and provided new insights for new drug development. In our future work, we will study the mechanism of folic acid on SARS-CoV-2 N.
Small molecule inhibitors of cyclin-dependent kinase 9 for cancer therapy
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Cyclin-dependent kinases (CDKs) form heterodimers with a specific family of proteins called cyclins. These functional CDK–cyclin complexes regulate cell cycle progression and gene transcription1. CDK9 is a member of the CDK family; it dimerises with cyclin T to form the positive transcription elongation factor b (p-TEFb) complex2,3. This complex stimulates transcription elongation through phosphorylation of the C-terminus domain (CTD) subunit of RNA polymerase II at Ser24. CDK9 plays a vital role in controlling the transcription of a number of genes, including Myc, a proto-oncogene that regulates processes required for cell growth and cell cycle progression, and Mcl-1, an anti-apoptotic member of the Bcl-2 family that enhances cell survival5. Therefore, CDK9 inhibition reduces messenger RNA (mRNA) transcription and prevents the expression of target genes (e.g. Myc and Mcl-1), which together regulate proliferation and cancer cells survival.