Cell structure, function and adaptation
C. Simon Herrington in Muir's Textbook of Pathology, 2020
The half-life of cellular proteins varies from seconds to months or years. The haemoglobin protein in red blood cells lasts for more than 100 days before the cell is removed from the circulation. The regulation of cellular proteins is a complex and important process for cell viability and function. If damaged protein accumulates it may inhibit normal protein function or injure the cell directly. Genetic abnormalities resulting in abnormal proteins are implicated in many diseases. In cystic fibrosis (see Chapter 8) a transmembrane chloride channel is dysfunctional, and this results in abnormal mucus secretion that leads to the phenotype seen clinically. In storage diseases, such as α1-antitrypsin disease, an abnormal protein is produced that cannot be efficiently secreted from the cell. The protein accumulates and can cause damage to the liver cells resulting in hepatitis, which may progress to cirrhosis (see Chapter 11). In addition, the absence of functional anti-protease in plasma leads to an increased risk of emphysema developing in the lungs (see Chapter 8). Mutation of tumour-suppressor genes can result in the formation of proteins with abnormal folding characteristics. Sometimes these inhibit the function of the corresponding normal protein (a dominant negative effect) and so contribute to the pathogenesis of cancer (see Chapter 6). Normally, damaged protein is marked for degradation by being bound to a carrier protein called ubiquitin, a process known as ubiquitination. This ubiquitinated protein is then removed from the cellular pool and degraded in the proteasome.
Proteasome and Protease Inhibitors
Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey in Innovative Leukemia and Lymphoma Therapy, 2019
Proteasomes are among the most ingenuous key regulators of the functioning cell. The proteasome is responsible for degradation of many intracellular proteins, thereby helping maintain the cellular homeostasis during biological processes such as cell cycle, signal transduction, response to stress and gene transcription. Among other functions, the proteasomal complex rapidly turns over misfolded proteins to avoid accumulation of dysfunctional proteins (5–7). Furthermore, the proteasome generates small peptides to initiate immune responses. These peptides bind to major histocompatibility complex (MHC) class I molecules and are transported to the plasma membrane. If the immune system does not tolerate the displayed peptide, cytolytic CD8 T-lymphocytes will eradicate the cell (8).
Modulating Cytolytic Responses to Infectious Pathogens
Thomas F. Kresina in Immune Modulating Agents, 2020
Major histocompatibility complex class I restricted antigen presentation primarily involves the MHC class I heavy chain binding peptides which have been generated within the cytoplasm of the cell. Several lines of evidence implicate the proteasome as involved in this degradation of cytosolic proteins for antigen presentation. First, genes encoding for two of the proteasome’s subunits, low-molecular-weight protein (LMP)-2 and LMP-7, are located within the MHC class II region [2,3]. Second, the proteasome is involved in both ubiquitin-dependent and ubiquitin-independent protein degradation pathways within the cell. Third, inhibitors of proteasome function, such as dipeptide aldehydes, can block the presentation of model peptides [4].
Bortezomib-loaded lipidic-nano drug delivery systems; formulation, therapeutic efficacy, and pharmacokinetics
Published in Journal of Microencapsulation, 2021
Mohammad Mahmoudian, Hadi Valizadeh, Raimar Löbenberg, Parvin Zakeri-Milani
Proteasomes are intracellular complexes, which are responsible for degrading the damaged and misfolded intracellular proteins. Genetic instability and rapid proliferation of cancer cells compared to normal cells make them more dependent on the function of the proteasome system. Hence, proteasome inhibitors are considered as an innovative target for cancer therapy (Voorhees et al.2003, Wu et al. 2010, Kaplan et al.2017, Manasanch and Orlowski 2017). Bortezomib (BTZ) is the first US Food and Drug Administration approved proteasome inhibitor for the treatment of multiple myeloma and mantle cell lymphoma. Besides the therapeutic efficacy of BTZ, its severe side effects (mainly included; peripheral neuropathy, gastrointestinal toxicity, and viral infections) is considered as a major dose-limiting factor, which restricts the feasibility of prolonged treatment (Moreau et al. 2011, Gandolfi et al. 2017, Mohan et al. 2017).
A comprehensive overview of daratumumab and carfilzomib and the recently approved daratumumab, carfilzomib and dexamethasone regimen in relapsed/refractory multiple myeloma
Published in Expert Review of Hematology, 2021
Shambavi Richard, Sundar Jagannath, Hearn Jay Cho, Samir Parekh, Deepu Madduri, Joshua Richter, Ajai Chari
Proteasomes are responsible for degrading or processing intracellular proteins that have been ubiquitylated. Proteasomal inhibition leads to the accumulation of intracellular proteins, resulting in cell death [36–38] and is a highly effective treatment for myeloma. Carfilzomib is a next-generation highly specific, novel proteasome inhibitor (Figure 2). It is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the amino (NH2) end of a polypeptide chain (N-terminal) threonine-containing active sites of the 20S proteasome. Like bortezomib, carfilzomib targets the chymotrypsin-like activity of the 20S proteasome. However, it is structurally and mechanistically different, has improved specificity for the proteasome, and has less off-target activity [39]. This selectivity may be responsible for the reductions in myelosuppression and neuropathy observed in preclinical studies comparing carfilzomib with bortezomib [40]. The mechanism of cardiotoxicity of PIs is not completely known. Some hypotheses are that proteasomal inhibition may lead to direct apoptosis of cardiomyocytes and endothelial progenitor cells and increased oxidative stress on cardiac myocytes. Additionally, endothelial effects of proteasomal inhibition resulting in hypertension (HTN) and vascular dysfunction and an increase in coronary vascular tone and reactivity may also contribute [41–44].
Research progress on therapeutic targeting of quiescent cancer cells
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Jinhua Zhang, Jing Si, Lu Gan, Cuixia Di, Yi Xie, Chao Sun, Hongyan Li, Menghuan Guo, Hong Zhang
The ubiquitin-proteasome system (UPS) is essential for degradation of aberrantly folded proteins and short-lived proteins involved in cell cycle progression, apoptosis, and signal transduction [5,56,57]. Tumor cells utilize UPS to achieve aberrant proliferation and survival [58]. Earlier findings support the utility of proteasomes as potential drug targets for some cancer types. Proteasome storage granules (PSG) enhance resistance to genotoxic stress and confer cell fitness during aging [59]. Upon entry of Saccharomyces cerevisiae into the stationary phase, massive re-localization of proteasome subunits occurs from the nucleus into motile cytosolic granules, thereby triggering PSG formation. This phenomenon is rapidly and completely reversed upon exit from quiescence [59,60]. Notably, ubiquitin is involved in regulating proteasome dynamics between proliferation and quiescence in yeast [59]. In addition, Spg5, a quiescence-specific positive regulator of the proteasome, directly binds to components of the proteasome and governs its function in quiescence [56].
Related Knowledge Centers
- Chemical Reaction
- Enzyme
- Peptide Bond
- Protease
- Protein
- Protein Folding
- Proteolysis
- Ubiquitin
- Protein Complex
- Cell