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Pathogenesis: Molecular mechanisms of osteoporosis
Published in Peter V. Giannoudis, Thomas A. Einhorn, Surgical and Medical Treatment of Osteoporosis, 2020
Anastasia E. Markatseli, Theodora E. Markatseli, Alexandros A. Drosos
When the signal in the Wnt pathway is absent, β-catenin binds to the complex consisting of the proteins axin, APC, Dsh, and GSK3β, and subsequently, β-catenin is phosphorylated by GSK3β kinase, resulting in reduced levels of free β-catenin in the cytoplasm. Phosphorylated β-catenin is degraded through the ubiquitin/proteasome pathway from the F-box protein and ligases E2 (250–252).
The mitotic phase of spermatogenesis
Published in C. Yan Cheng, Spermatogenesis, 2018
The functional role of UPS in the mitotic phase of spermatogenesis can be highlighted by the E3 ligases involved in Skp1-Cullin-F-box (SCF) complex. The SCF complex is one of the major ubiquitin ligases complex required for cell cycle progression.78 The F-box protein component of the SCF complex is an E3 ligase that binds to the complex and controls the substrate recognition. Various F-box proteins can bind to the SCF complex, and this variability allows the SCF complex to target a range of substrates.79 Skp2 is an F-box protein required for S phase progression by target degradation of cyclin-dependent kinase inhibitor p27.80 A study has shown that knockout of Skp2 reduces fertility, which is associated with the progressive loss of spermatogonia and an increase in apoptosis. More importantly, double knockout of Skp2 and p27 partially restored the number of germ cells and the fertility outcome, suggesting that Skp2 is required for the maintenance of spermatogonia by targeting p27.81
Neurobiology of Mood Disorders
Published in Dr. Ather Muneer, Mood Disorders, 2018
Mice engineered bearing other circadian gene mutations exhibit comparable behavioral phenotypes. These include transgenic mice overexpressing GSK3β and those with a mutation in F-box protein 3 (Fbxl3, a protein that targets CRY for degradation). Sirtuin 1 (SIRT1) is a histone deacetylase which antagonizes the actions of transcription factors CLOCK and BMAL1. SIRT1 knockout mice also have a decrease in anxiety-like behavior at baseline, and lowered depression-related behavior following chronic social defeat paradigm. Overexpression of SIRT1 leads to the opposite effect. SIRT1 knockout should lead to increased CLOCK activity yet the mutant mouse has a similar manic-like phenotype, suggesting that perhaps any circadian gene mutation will lead to the same behavioral profile.11 However, while PER2 knockout mice also have reduced immobility in the Porsolt’s forced swim test, mice with mutations in both PER1 and PER2 (double mutants) have a normal locomotor response in the novelty seeking test, and an increase in anxiety-related behavior which is the opposite of what is observed in the ClockΔ19 and other mutant mice.12 Therefore, the observed rodent behavior in a variety of investigational conditions suggests that circadian genes have some specificity in their function and the same phenotype is not produced with the mutation of any circadian factor. Of course, some of these proteins are involved in other processes besides daily rhythm regulation and it is conceivable that the mood and anxiety-related behavioral phenotypes are due to alterations in other physiological systems.
PLK4: a link between centriole biogenesis and cancer
Published in Expert Opinion on Therapeutic Targets, 2018
Radhika Radha Maniswami, Seema Prashanth, Archana Venkataramana Karanth, Sindhu Koushik, Hemalatha Govindaraj, Ramesh Mullangi, Sriram Rajagopal, Sooriya Kumar Jegatheesan
Destabilization of kinase-active PLK4 is mediated by autophosphorylation at 13 critical phosphorylation sites present within the 24-aa PLK4 phosphodegron motif located in the first PEST domain. More importantly, trans-autophosphorylation at S285 present in the degron motif is critical for PLK4 destruction, while phosphorylation at T289 increases degradation efficiency. Furthermore, these phosphorylation events create a binding site for SCF/β-TRCP E3 ubiquitin ligase complex [48,141,142]. The SCF complex consists of SKP1, CUL1, RBX1, and a variable F-box protein. Cul1 functions as a scaffolding protein which binds to Skp1 and F-box protein at its N-terminus and RBX1 at its C-terminus. The F-box protein dictates the substrate specificity of the SCF complex [143]. Slimb and β-TRCP are the F-box proteins in Drosophila and vertebrates, respectively. Binding of SCF-complex leads to PB1 ubiquitination and tags PLK4 for degradation by 26S proteasome [54]. To summarize, kinase activity of PLK4 autoregulates its own stability in order to safeguard mitotic fidelity. PLK4 can thus be termed as a suicide kinase that is active on synthesis and then undergoes robust autodestruction.
Exploring the role of circadian clock gene and association with cancer pathophysiology
Published in Chronobiology International, 2020
Mahtab Keshvari, Mahdieh Nejadtaghi, Farnaz Hosseini-Beheshti, Ali Rastqar, Niraj Patel
Before DBT begins phosphorylating PER, a different protein called NEMO/NLK kinase begins phosphorylating PER at its per-short domain. This phosphorylation stimulates DBT to begin phosphorylating PER at multiple nearby sites. In total, there are about 25–30 phosphorylation sites on PER (Chiu et al. 2011). The phosphorylated PER binds to the F-box protein SLIMB and then targeted for degradation through the ubiquitin-proteasome pathway (Syed et al. 2011). Therefore, the phosphorylation of PER by DBT leads to a decrease in PER abundance, which is a necessary step in the function of the organism’s internal clock (Syed et al. 2011).
Endoplasmic reticulum stress-related signature predicts prognosis and immune infiltration analysis in acute myeloid leukemia
Published in Hematology, 2023
Lu Dong, Haili Wang, Zefeng Miao, Yanhui Yu, Dongzheng Gai, Guoxiang Zhang, Li Ge, Xuliang Shen
In this study, ER stress-related genes were analyzed in AML. First, 18 ER stress-related genes were identified, including 8 downregulated genes and 10 downregulated genes. A comprehensive network was constructed, including 38 pairs of gene and protein relationships, 67 pairs of co-expression relationships A total of 5 CC, 8 MF, 17 BP, and 2 KEGG pathways were enriched. The most enriched signaling pathways in CC were ‘endoplasmic reticulum,’ ‘integral component of membrane,’ and ‘endoplasmic reticulum membrane;’ those in MF were ‘protein kinase binding,’ ‘ubiquitin protein ligase activity,’ ‘ubiquitin protein ligase binding,’ and ‘enzyme;’ those in BP were ‘endoplasmic reticulum unfolded protein response,’ ‘ubiquitin-dependent ERAD pathway,’ and ‘cellular response to glucose starvation.’ ‘Protein processing in endoplasmic reticulum’ and ‘p53 signaling pathway’ were enriched in KEGG. Further, 10 ER stress-related genes were optimized, among which MBTPS1, TBL2, VAPB, and PDIA4 were protective factors, and FBXO44, TRIB3, RNF139, BRSK2, TRIM25, and FKBP14 were risk factors. We then combined the DEGs with their corresponding clinical information to establish an RS model. In the prognostic prediction mode, MBTPS1 and FBXO44 had the greatest impact on prognosis. The higher the expression level of MBTPS1, the better the prognosis. The MBTPS1 gene, also known as the membrane-bound transcription factor peptidase site 1 gene, encodes Site-1 protease (S1P). S1P regulates lipogenesis, ER function, lysosomes, and biogenesis in mice and cultured cells. Studies have found [33] that deletion of MBTPS1 can impair ER function. The investigators also developed a predictive model that included six membrane protein genes in patients with AML without cytogenetic abnormalities, among which MBTPS1 was a risk factor. However, the higher the expression level of FBXO44, the worse the prognosis. FBXO44 belongs to the F-box protein family (FBA family) and shares a conserved G domain for substrate binding. In addition to sequence homology, all members of the FBA family, except FBXO44, can recognize the glycosylation substrate FBXO44, which has a substrate-recognition function during ubiquitin-mediated proteolysis [34–36]. A misfolded protein response occurs when the ER lumen misfolds or when excessive protein synthesis occurs. Studies [37] have shown that FBXO44 is an E3 ubiquitin ligase responsible for BRCA1 degradation. FBXO44 promotes the silencing of DNA replication-coupled repetitive elements in cancer cells [38].