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Responses to Muscular Exercise, Heat Shock Proteins as Regulators of Inflammation, and Mitochondrial Quality Control
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Alex T. Von Schulze, Paige C. Geiger
HSPs have the additional ability to tag and initiate the degradation of damaged proteins via the UPS. The UPS tags damaged or aggregated proteins with ubiquitin to target them for degradation via the proteasome (22). HSP70 and HSP90 are linked to the UPS via the co-chaperone carboxyl terminus of Hsc70 interacting protein (CHIP) and ubiquitin conjugating enzyme E2 N (UBE2N) (20, 98). CHIP, an E3 ubiquitin ligase, contains N-terminal binding domains for both HSP70 and HSP90. Upon HSP70 or HSP90 binding with the damaged target protein, the protein-bound HSP complexes are recruited to CHIP (12). This CHIP:HSP:Protein complex then interacts with the UBEN2, allowing for the transfer and ligation of ubiquitin onto target proteins (98). Once the substrate protein is tagged with ubiquitin, the nucleotide exchange factor, Bcl‐2‐associated athanogene 1 (BAG1), binds to the CHIP:HSP:Protein-ub complex allowing for proteasomal recruitment and eventual substrate release (54). In this way, HSP40, HSP70, and HSP90 work with CHIP synergistically to degrade proteins that are beyond repair.
Genes involved in glucocorticoid receptor signalling affect susceptibility to mood disorders
Published in The World Journal of Biological Psychiatry, 2021
Dawid Szczepankiewicz, Beata Narożna, Piotr Celichowski, Kosma Sakrajda, Paweł Kołodziejski, Ewa Banach, Przemysław Zakowicz, Ewa Pruszyńska-Oszmałek, Joanna Pawlak, Monika Wiłkość, Monika Dmitrzak-Węglarz, Maria Skibińska, Alicja Bejger, Joanna Twarowska-Hauser, Janusz K. Rybakowski, Leszek Nogowski, Aleksandra Szczepankiewicz
GR receptor exists in two isoforms: active α isoform can bind the ligand (steroid) or inactive β isoform, which represses GRα activity and the translocation of ligand-receptor complex to the nucleus thus blocking its biological activity. For proper function, GR requires a hetero-complex of proteins that include chaperones (heat shock proteins 70, 90, 40 and heat shock organising protein), co-chaperones (FKBP5, FKBP4) and other proteins influencing its biological activity (stress-induced phosphoprotein 1 (STIP1), BCL2 associated athanogene 1 (BAG1), dual specificity phosphatase 1 (DUSP1), glucocorticoid-induced transcript 1 (GLCCL1)) and regulating the alternative splicing of the receptor (serine and arginine-rich splicing factors, SRSFs). The previous observations showed that the latter is crucial for proper isoforms ratio and GR biological activity (Jain et al. 2012).
Shining a light on cell signaling in leukemia through proteomics: relevance for the clinic
Published in Expert Review of Proteomics, 2018
Fieke W. Hoff, Chenyue W. Hu, Amina A. Qutub, Eveline S. J. M. de Bont, Terzah M. Horton, Steven M. Kornblau
The advantage of RPPA is the ability to simultaneously measure the expression levels of thousands of samples. Because of its high throughput capacity, RPPA are highly applicable to correlate protein expression in multiple patients with varying clinical characteristics, cytogenetic genotypes, and disease outcome. Accordi et al. used the RPPA technology to profile 92 proteins in a cohort of 118 newly diagnosed pediatric B-cell precursor ALL patients [25]. Their goal was to map pathway activation changes in LCK kinase in patients that responded poorly to prednisolone compared to those with a good response. In addition, they found that Cyclin E1 was an adverse prognostic factor for relapse free survival. Milani et al. [26] performed a RPPA phospho–proteomic screen on 98 pediatric T-cell ALL samples and identified a large variation in protein kinase C alpha (PKCα) phosphorylation at serine 657. Real-time quantitative polymerase chain reaction verified downregulation of PKCα in a cohort of 173 patients as a prognostic marker for increased cumulative risk of relapse. Another study reported that BCL-2-Associated Athanogene 1 (BAG1) was over expressed in 87 of the 99 analyzed adult AML patients compared to healthy controls and that patients with very high BAG1 levels had a decreased 5-year event-free survival [27].
The effects of ovarian hormones on stressor-induced hormonal responses, glucocorticoid receptor expression and translocation, and genes related to receptor signaling in adult female rats
Published in Stress, 2018
Matthew R. Green, Marina L. Marcolin, Cheryl M. McCormick
To characterize the actions of estradiol on HPA function and GR signaling, we investigated its effects on plasma corticosterone concentration, GR translocation and the expression of genes that code for corticosteroid receptors, co-chaperones, and a co-activator. We administered estradiol alone or in combination with progesterone to ovariectomized females and measured protein and mRNA expression in the hippocampus because of its involvement in negative feedback (Herman et al., 2012). Progesterone treatment was included because it was found to mitigate the effects of estradiol on HPA activity and feedback (Viau & Meaney, 1991) and can affect corticosteroid receptor binding (Carey et al., 1995). We hypothesized that estradiol, alone or in combination with progesterone, would increase baseline and post-stress corticosterone, consistent with past studies, and reduce expression of cytosolic GR in the hippocampus as well as stressor-induced GR translocation. Further, we hypothesized that baseline mRNA expression of corticosteroid receptors would be concomitantly reduced, whereas genes coding for anti-translocation (e.g. Fkbp5 and Bag1 [codes for BCL-2 associated athanogene 1]) and pro-translocation (Fkbp4 [codes for FK506 binding protein 52]) co-chaperones may be augmented and dampened by estradiol treatment, respectively.