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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.
Identification of hub genes, miRNAs and regulatory factors relevant for Duchenne muscular dystrophy by bioinformatics analysis
Published in International Journal of Neuroscience, 2022
Meng-Xi Xiu, Bin Zeng, Bo-Hai Kuang
According to the constructed PPI network, three DEGs with high degrees were identified as hub genes: HERC5, SKP2 and FBXW5. All three hub genes were located in Module 1, which is closely related to ubiquitin-mediated autophagy and protein proteolysis, pathological processes that cause myofiber degeneration and muscle weakness in DMD [23]. HERC5 is a HECT E3 ubiquitin ligase that is upregulated in DMD-affected skeletal muscle. Consistent with our study, HERC5 was found to be significantly overexpressed (62-fold) in skeletal muscle affected by dermatomyositis (DM) with perifascicular atrophy compared to non-DM skeletal muscle, suggesting that HERC5 can potentially promote muscular atrophy [24]. SKP2 and FBXW5 are F-box proteins within the SCF E3 ubiquitin ligase complex that induces proteasomal degradation of several cell cycle proteins and control cellular proliferation [25–27]. They were found to be up- and downregulated in DMD-affected skeletal muscle, respectively. The overexpression of SKP2 plays a major role in senescence-associated autophagy, which leads to myocardial autophagic dysfunction [28]. In addition, the loss-of-function of FBXW5 in Parkinson’s disease (PD) contributes to dysregulated autophagy, promoting neurodegeneration [29]. However, the role of SKP2 and FBXW5 in skeletal muscle and how their dysregulation affects DMD progression remains unclear.
Isoform-specific activities of the regulatory subunits of phosphatidylinositol 3-kinases – potentially novel therapeutic targets
Published in Expert Opinion on Therapeutic Targets, 2018
Yoshihiro Ito, Jonathan R. Hart, Peter K. Vogt
Whereas many details of the significant protein–protein interactions involving p85α are known, our knowledge of p85β is much more fragmentary. One exception is the interaction with the XBP1-BRD7 complex [38]. A second one is the binding to the F-box protein FBXL2 and the phosphatase PTLP1 which control cellular p85β levels by mediating proteolytic degradation. This mechanism is specific for p85β and is not observed with p85α [53]. Possibly related to this p85β regulating pathway that results in inhibition of PI3K signaling is an interaction between PTEN and p85β [54]. PTEN has been reported to dephosphorylate p85β. Phosphorylation of p85β at Y655 interferes with FBXL2 binding and stabilizes p85β, and dephosphorylation would enhance degradation of p85β. Additional p85β activities were characterized in B- and T-cells where knockout of p85β has an unexpected positive effect on signaling and cell proliferation [55–57].
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.