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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
While all three processes are tightly regulated, the rate-limiting step for translational control occurs at the initiation step. Translation initiation is a multi-step process regulated by eukaryotic initiation factors (eIFs) and culminates in formation of the 80S initiation complex. Prior to translation, the subunits of the ribosome are separate and the 40S subunit must be ‘primed’ by binding of a transfer RNA (tRNA). The tRNA contains the complementary sequence for the AUG start codon of mRNA and is also attached to the amino acid methionine. Proteins are synthesised beginning from the amine N-terminal and ending with a carboxyl C-terminal; therefore, all proteins begin with a methionine residue, although this is often removed after translation. The priming of the 40S ribosome is regulated in part by eIF3 and creates a 43S pre-initiation complex. Next eIF4 guides the 5’-end (named 5’-cap) of mRNA into the 43S complex and the ribosome proceeds along the mRNA until the start codon is found. Other eIFs then recruit the 60S subunit to create the 80S initiation complex, and synthesis of the polypeptide chain begins.
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In eukaryotic organisms, pre-mRNA is transcribed in the nucleus. Introns are then spliced out, and the mature mRNA exported from the nucleus to the cytoplasm. The small subunit of the ribosome usually starts by binding to one end of the mRNA and is joined there by various other eukaryotic initiation factors, thus forming the initiation complex. The initiation complex scans along the mRNA strand until it reaches a start codon, and then the large subunit of the ribosome attaches to the small subunit and translation of a protein begins. Backbone-modified oligomers (Figure 5.95) can bind to the RNA and block this process. Structures of peptide nucleic acids (PNAs), Morpholino Oligonucleotides and the ribose sugar modifications of locked nucleic acids (LNAs) in comparison to DNA.
Soluble Mediators of Cellular Cooperation: The Cytokines
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
Biological activities. Type 1 IFNs activate several non-specific antiviral mechanisms. IFNs induce the production of two enzymes (and others, less well-characterized) which may affect synthesis of viral proteins during infection. These are a protein kinase, and a 2’–5’ oligoadenylate synthetase. Double-stranded RNA (dsRNA) appears to be required for activity of these proteins. While dsRNA does not normally occur in eukaryotic cells, it is found as an intermediate in replication of many viruses. The protein kinase inactivates eukaryotic initiation factor-2a (eIF-2a), thereby inhibiting protein synthesis. The 2’-5’ oligo-A synthetase forms 2’-5’ oligoadenylic acid, a cofactor needed for activity of an endogenous ribonuclease, RNAse L. RNAse L degrades messenger and ribosomal RNAs.
Protective role of PERK-eIF2α-ATF4 pathway in chronic renal failure induced injury of rat hippocampal neurons
Published in International Journal of Neuroscience, 2023
Qi Chen, Jingjing Min, Ming Zhu, Zhanqin Shi, Pingping Chen, Lingyan Ren, Xiaoyi Wang
ERS is mainly mediated by three proteins on the endoplasmic reticulum omentum: PERK,9 ATF6 (activating transcription factor 6)10–13 and inositol enzyme1 (inositol requiring enzyme 1, Ire1),14,15 of which PERK is involved in the PERK-eIF2α-ATF4 pathway. When ERS occurs, a large number of unfolded or misfolded proteins bind to Bip (binding immunoglobulin protein), and PERK is thereafter released from the complex and activated. PERK activation leads to the phosphorylation of eIF2α (Eukaryotic initiation factor 2α), and phosphorylated eIF2α inhibits ribosome assembly and prevents protein translation from initiation. As a consequence, protein synthesis and energy consumption as well as the concentration of misfolded proteins in the endoplasmic reticulum are reduced, which thereby maintains the stability of the internal environment.16,17 PERK-eIF2α signaling pathway reduces the need for the folding of newly synthesized proteins in the endoplasmic reticulum, while it also increases the transcription levels of certain genes specifically through some fine-tuning mechanisms, mainly by upregulation of ATF4.18
Is chronic pain as an autoimmune disease?
Published in Canadian Journal of Pain, 2022
A number of reports support that the X chromosome is associated with higher rates of pain2,4,52,53 and posttraumatic stress as observed in females compared to males.54,55 Sex differences have also been described in animal models, with increased hyperalgesia56,57 and insufficient fear extinction reported in females.58,59 Investigations have shown that a large number of individuals who develop chronic musculoskeletal pain60,61 and/or symptoms of posttraumatic stress62 after an automobile accident are females. These females who have XIST are found to have dysregulated chronic pain.48 An investigative study by Yu et al.63 observed that, during the initial stages following a car accident, 40 genes originating from the X chromosome were differentially expressed in females and were responsible for the development later of chronic musculoskeletal pain and/or signs of posttraumatic stress compared to those who recuperated.63 By comparison, 25 X chromosome genes were differentially expressed males, with the authors noting that this repertoire was different from those identified in the set from females. In males, two well-defined clusters were identified by pathway analysis and were enhanced for genes previously shown to not be responsible for X chromosome inactivation. These group of genes were based on upregulated gene expression associated with the eukaryotic initiation factor 2 signaling pathway or IL‐2 pathway.63
Pharmacological management of male breast cancer
Published in Expert Opinion on Pharmacotherapy, 2020
Bruno A. Duso, Dario Trapani, Antonio Marra, Paolo D’Amico, Elena Guerini Rocco, Nicola Fusco, Luca Mazzarella, Carmen Criscitiello, Angela Esposito, Giuseppe Curigliano
The high activity of the eukaryotic initiation factor 4E (eIF4E) pathway is related to a poor prognosis in FeBC, where this molecular mechanism is considered a bona fide therapeutic target [30]. The activity of the eIF4E pathway is controlled by the eIF4E-binding proteins and is regulated by mTORC1 complex-mediated phosphorylation. In MaBC, the expression of the four key proteins belonging to this translational machinery (i.e. eIF4E, 4E-BP1, 4E-BP2 and p4E-BP1) is extremely heterogeneous. Among them, p4E-BP1 expression has been particular associated with poor prognosis. Despite no available data on the clinical actionability of these biomarkers in MaBC, the expression of p4E-BP1 may identify a subset of patients with a rationale for being enrolled on therapies targeting elements of the mTOR pathway.