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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
This array of sensor proteins acting as, and in concert with, primary and secondary messengers then transduce these signals arising from metabolic, mechanical, hormonal and neuronal stimuli through complex signal transduction networks (Step 3 – ‘signal transduction’). This signal transduction of molecular information mainly includes protein-protein interactions and posttranslational modifications (e.g. phosphorylation and acetylation) that lead to the activation and/or repression of an array of proteins that relay the sensed molecular signals inside the cell and are ultimately coupled to a myriad of effector proteins (Step 4 – ‘effectors’). These effector proteins, such as transcription factors and coregulators, and translation initiation and elongation factors, regulate transcriptional processes (Step 5 – ‘transcription’), and the regulation of protein translation (Step 6 – ‘translation’), respectively.
Current and emerging pharmacological agents in the treatment of osteoporosis
Published in Peter V. Giannoudis, Thomas A. Einhorn, Surgical and Medical Treatment of Osteoporosis, 2020
James X. Liu, Thomas A. Einhorn
The differential pharmacologic effects of SERMs are due to the three primary mechanisms: differential expression of estrogen receptors depending on the target tissue, differential conformation of the estrogen receptor itself, and differential estrogen receptor binding to coregulator proteins, of which more than 20 have been previously described (7). Coregulator proteins primarily function as activating or repressing transcriptional regulators that modulate receptor activity. The action of SERMs is related to the ligand binding domain of the estrogen receptor; the presence of coactivating or corepressing interaction on the receptor surface determines whether the estrogen receptor ultimately activates the DNA estrogen-responding element or promotes proteasomal release (8). Over the past 10 years, there has been an expansion in the number of coregulator families of estrogen receptors being defined. The intracellular mechanisms are also likely to be influenced by other tissue-related proteins that alter gene transcription and translation through phosphorylation. Although the mechanism of SERMs on bone, breast, and endometrial tissue has been described, many of the exact subcellular processes are still being evaluated (8).
Regulation of the Pituitary Gland by Dopamine
Published in Nira Ben-Jonathan, Dopamine, 2020
As illustrated in Figure 5.8B, distinct pituitary cell types emerge from a common primordium in response to opposing signaling gradients that originate from organizing centers. Terminal cell type differentiation requires selective gene activation and long-term active repression. These are mediated by cell type-specific and promoter-specific recruitment of coregulatory complexes. Thyrotrophs, lactotrophs and somatotrophs are derived from a common lineage, determined by the transcription factors Prop-1 and Pit-1, while independent lineages lead to the formation of corticotrophs and gonadotrophs. Overall, pituitary organogenesis is a complex and tightly regulated temporal and spatial process that depends on interactions between transcription factors such as Prop1, Pit1 (Pou1f1), Hesx1, Lhx3, and Lhx4. Mutations in these genes can result in various forms of hypopituitarism and can be associated with structural alterations that cause congenital forms of panhypopituitarism.
Experience and activity-dependent control of glucocorticoid receptors during the stress response in large-scale brain networks
Published in Stress, 2021
Damien Huzard, Virginie Rappeneau, Onno C. Meijer, Chadi Touma, Margarita Arango-Lievano, Michael J. Garabedian, Freddy Jeanneteau
Cellular history of excitation and exposure to stress mediators may define the accessibility of ligands (glucocorticoids, nucleic acids, and co-regulators) to the core functional units. For the rapid non-genomic effects, the interactors of GR and MR are ill-defined. For transcriptional effects, the basic effector mechanism can be conceptually reduced to the ligand, the receptor, the DNA, and the transcriptional coregulators that interact directly with the receptors (Monczor et al., 2019). Of note, while the stress-induced glucocorticoid signal is predicted to mainly affect GR occupancy (Reul & de Kloet, 1985), GR and MR share many of their DNA binding sites (van Weert et al., 2017) and potential target genes, including often used readouts for receptor activity such as the Fkbp5 gene (van Weert et al., 2019). This implies that GR/MR signaling prior to a stressor will interact with stress-induced GR signaling. GR/MR and other nuclear receptors also share an important part of their coregulator repertoire (Broekema et al., 2018; Meijer et al., 2005). This points to intrinsic interactions between both GR and MR, and between glucocorticoids and other steroid signaling pathways. However, these may be considered stable over the time frame of hours, or often longer periods of time.
Androgen receptor gene microsatellite polymorphism is associated with muscle mass and strength in bodybuilders and power athlete status
Published in Annals of Human Biology, 2021
João Paulo L. F. Guilherme, Yulia V. Shikhova, Rimma R. Dondukovskaya, Alexandra A. Topanova, Ekaterina A. Semenova, Irina V. Astratenkova, Ildus I. Ahmetov
Androgen binding to the AR induces a conformational change in the structure of the receptor that facilitates molecular communication between the NH2-terminal domain and the COOH-terminal domain, generating a (N/C) terminus interaction that is required for AR dimerisation and is fundamental for the binding to AREs (He et al. 1999). DNA binding causes the N/C interaction to be lost, allowing the recruitment of coactivators to initiate transcription (van Royen et al. 2012). A longer PolyGln chain may influence N/C interaction and the ability to recruit coregulators and components of the AR-mediated transcription machinery (Buchanan et al. 2004). In vitro analyses have shown that the elongation of the PolyGln chain results in a linear decrease in the AR transcriptional competence in mammalian cell lines (Chamberlain et al. 1994; Kazemi-Esfarjani et al. 1995; Tut et al. 1997; Irvine et al. 2000). However, this effect has been shown to be cell (or tissue) specific (Beilin et al. 2000), presumably due to distinct profiles of AR coregulator proteins (Heemers and Tindall 2007). For example, while the levels of AR-mediated mRNA in prostate cells appear to correlate inversely with PolyGln length (Albertelli et al. 2006), the opposite has been seen in myoblasts (Sheppard et al. 2011).
The effects of all-trans retinoic acid on estrogen receptor signaling in the estrogen-sensitive MCF/BUS subline
Published in Journal of Receptors and Signal Transduction, 2018
Ignacio Miro Estruch, Laura H. J. de Haan, Diana Melchers, René Houtman, Jochem Louisse, John P. Groten, Ivonne M. C. M. Rietjens
ERα-mediated gene expression and the consequent proliferation of breast cancer cells have been reported to be affected upon exposure to RAR agonists [5,8,9,17]. However, the underlying molecular mechanisms of this interplay between ER and RAR signaling are not completely understood. The objective of the present study was to investigate the possible effects of the pan-agonist AtRA on ERα signaling by using two cell models that have not been used before for this purpose, being a highly E2-responsive breast cancer MCF7 subline (MCF7/BUS) and the reporter gene cell line U2OS-ERα-Luc. To do so, a battery of assays testing several endpoints related to the ERα pathway such as cell proliferation, gene expression, coregulator binding and sub-cellular localization were carried out. Using these techniques, this study investigated possible modes of action of AtRA on the pro-proliferative ERα signaling, including (a) action as a direct ligand, (b) effects on gene expression, (c) effects on coregulator interactions and (d) effects on ERα subcellular localization.