Signal transduction and exercise
Adam P. Sharples, James P. Morton, Henning Wackerhage in Molecular Exercise Physiology, 2022
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.
Molecular diagnosis of endometriosis
Carlos Simón, Linda C. Giudice in The Endometrial Factor, 2017
Nuclear receptor regulation of transcription requires the action of nuclear coregulators that enhance (coactivator) (NCOAs) or repress (corepressor) (NCORs) transcriptional activity (65,66). Tissue and cell-type differences in coregulator expression, and hence posttranslational modification, likely contribute to cell specificity of steroid hormone action (65). The nuclear receptors interact with DNA-methylating or -demethylating enzymes and histone-modifying enzymes in the transcriptional complex, and histone modification and DNA methylation are interconnected in regulating gene expression and chromatin remodeling (67). Endometrium being a steroid hormone-responsive tissue is heavily dependent on nuclear ER and PR interaction with coregulators, resulting in cyclic changes in cellular processes, including proliferation, apoptosis, differentiation, and angiogenesis. As discussed above, decreased expression of PRs and hypermethylation of the PGRB promoter in women with endometriosis have been reported (32,50). Aberrant levels of nuclear receptors and their coregulators in ectopic endometriotic lesions have been implicated in the progression of endometriosis (reviewed in (68)). In the setting of endometriosis, our group found increased expression of NCOR1 in secretory phase eutopic endometrium, most likely downregulating genes targeted by P4 (60), while increased NCOA1 in both proliferative endometrium (PE) and early secretory endometrium (ESE) from women with endometriosis warrants further investigation (Figure 4.2).
Individualization of Endocrine Therapy in Breast Cancer
Brian Leyland-Jones in Pharmacogenetics of Breast Cancer, 2020
The recruitment of coactivators or corepressors to the ER determines the switch between ER activation and repression. In addition, the coordinated action of ligand, ER, and coregulators determines which genes are transcribed or repressed depending on the cellular context and thus which cells will or will not proliferate. The overall data indicate that intricate modulation of the ER-to-coregulator ratio in breast cancer cells could determine resistance to antiestrogens. For example, the coactivator SRC-1 activates ER in a ligand-independent manner while increasing 4OHT’s agonist activity (19). On the other hand, the corepressor SMRT blocks the agonist activity of 4OHT-induced by SRC-1 (20). The other member of the p160 coactivator family is amplified in breast cancer (AIB1, SRC-3, and RAC3). AIB1 mRNA was found to be amplified in 60% of breast cancers, and the protein product was found to be overexpressed in about 10% of tumors. Recently, an association was discovered between high AIB1 and human epidermal growth factor receptor 2 (HER2/neu), a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases and tamoxifen-resistant breast cancers (20). The potential mechanism for this resistance requires activation of the mitogen-activated protein kinase (MAPK) signaling cascade by HER2/neu, which in turn potentially phosphorylates and activates AIB1. Activated AIB1 in turn can convert 4OHT from an antiestrogen to an estrogen in regards to ERα activity. In contrast, low levels of N-CoR mRNA, a corepressor, have been implicated with resistance to tamoxifen (21). Therefore, the identification of abnormally expressed coregulators will probably assist in the design of future therapies that improve the efficacy of endocrine treatment without the development of resistance.
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.
The cellular and molecular effects of the androgen receptor agonist, Cl-4AS-1, on breast cancer cells
Published in Endocrine Research, 2018
Mamoun Ahram, Ebtihal Mustafa, Shatha Abu Hammad, Mariam Alhudhud, Randa Bawadi, Lubna Tahtamouni, Faisal Khatib, Malek Zihlif
Whereas DHT has a stimulatory effect on proliferation of MCF-7 and MDA-MB-453, Cl-4AS-1 inhibited proliferation of all breast cancer cell lines, including two other ones (T47D and ZR75-1), regardless of the subtype. It is not clear whether Cl-4AS-1 acts via the same pathway that suppresses cell growth in the different breast cancer cell types or not. SARMs, similar to SERMs, have a tendency to selectively bind coregulators.29 Such selectivity is governed by the conformational change induced by the natural ligand versus the tissue-selective modulator, the coactivator:corepressor ratio in cells, and the existence of external stimuli. In a previous study, we have shown that Cl-4AS-1 differentially alters expression of microRNA molecules in breast cancer cell lines including two of the same subtype.30 Unfortunately, no other molecular study has been conducted on this compound.
Myokine-mediated exercise effects: the role of myokine meteorin-like hormone (Metrnl)
Published in Growth Factors, 2021
Transcriptional coregulators are proteins that are involved in gene expression (Lempradl, Pospisilik, and Penninger 2015). Peroxisome-proliferator activated receptor γ coactivator 1 (PGC-1) family of coactivators are the main regulators of energy metabolism in many tissues, especially in tissues with high demands of energy (Puigserver et al. 1998). PGC-1family has three members of PGC-1α, PGC-1β and PRC (PGC-1-related coactivator) (Andersson and Scarpulla 2001; Lin, Puigserver, et al. 2002). Among this family, PGC-1α is the most studied in the fields of energy metabolism, cardiovascular disease, neurodegenerative diseases, skeletal muscle physiology, and even mood disorders (Lin, Wu, et al. 2002; Wu et al. 1999; Handschin et al. 2007). PGC-1α activity and expression are regulated by many and various stimuli in a tissue-specific manner (Fernandez-Marcos and Auwerx 2011). There are four PGC-1α variants of PGC-1α-1 (PGC-1α), PGC-1α-2, PGC-1α-3 and PGC-1α-4. PGC-1α-1 also known as PGC-1α is the most well-known isoform (Léveillé et al. 2020). PGC-1α expression in skeletal muscle has been shown to induce both local changes such as fuel supply, uptake and utilization and endocrine (systemic) effects by producing and secreting signalling molecules called myokines which creates a crosstalk between skeletal muscle and other tissues (Correia, Ferreira, and Ruas 2015). Different isoforms of PGC-1α control the production of different myokines. Spiegelman’s research team discovered that the expression of PGC-1α-4 in skeletal muscle stimulates increased mRNA and secretion of myokine Metrnl (Rao et al. 2014).
Related Knowledge Centers
- Corepressor
- DNA
- Molecular Biology
- Protein
- Chromatin
- Genetics
- Transcription Factor
- Transcription
- Coactivator
- Post-Translational Modification