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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
As mentioned previously, HSP induction occurs as a cellular stress response to stimuli such as exercise or oxidative stress. This induction is first initiated by the primary transcription factor for HSPs, heat shock factor 1 (HSF1), which trimerizes and undergoes nuclear translocation under stress (53, 78). In combination with the transcriptional co-activator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), HSF1 binds to its canonical DNA docking sites known as heat shock elements (HSEs), which act as promoter regions for HSP-related genes (78, 97). Upon the HSF1–PGC1α complex binding, HSF1 is phosphorylated and transcription is initiated (78). As with many other proteins, HSF1's activity is dependent on HSP content. Specifically, once enough HSPs (specifically HSP70) are translated, they in turn bind to HSF1, removing it from its DNA docking site and returning it to its monomeric form in the cytoplasm (78). PGC1α can also counter-regulate HSF1 through transcriptional repression (60). In this way, the stress response is a tightly regulated process coupled to cellular HSP and PGC1α content. Moreover, this increase in intracellular HSP content is critical for cell survival and proteostasis under stress.
Spermatogenesis, heat stress and male infertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Germ cells like somatic cells use heat shock proteins (HSPs) to act as molecular chaperones under normal circumstances and are essential for normal spermatogenesis by ensuring correct assembly and transport of proteins (28). An example of such a HSP is HSP70, the most abundant HSP. Under heat stress, heat shock factors (HSFs), a series of transcription factors, are activated (11). The HSF1 has a dual role to first stabilize and protect somatic cells (heat-resistant cells) but then to trigger apoptosis in germ cells such as primary spermatocytes (heat-sensitive cells) (11). Rather than to preserve germ cells following heat stress, HSF1 appears to trigger germ cell removal, perhaps due to damaged DNA. Widlak and Vydra (11) suggest that this may be due to the overproduction of sperm, and it may be better to just destroy these cells rather than chance the possibility of damaged DNA interfering with fertilization, embryo or fetal development. Even with this removal, we have observed that some sperm produced after heat stress do indeed have damaged DNA and reduced ability to sustain embryo development after fertilization (16,17).
Tyrosine Kinase Inhibitors: Targets Other Than FLT3, BCR-ABL, and c-KIT
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Suzanne R. Hayman, Judith E. Karp
A cell’s response to injury or environmental stresses such as heat, inflammation, chemotherapy, or the generation of reactive oxygen species (ROS) may result in cell death, either by apoptosis or necrosis. However, if the level of stress is relatively low, the cell may attempt to survive through the initiation of the heat shock or stress response. This is manifested by the suppression of most new protein synthesis, except for the upregulation of gene expression of Hsps. There are six major families of Hsps grouped according to their approximate weights in kDa (Hsp100, Hsp90, Hsp70, Hsp60, Hsp40, and small Hsps 10–28 kDa). Hsps and their homologs may be found in multiple intracellular compartments including the nucleus, cytosol, mitochondria, and endoplasmic reticulum. Most Hsps are both constitutively expressed and inducible, with increased gene expression resulting from the binding of heat shock transcription factors, particularly heat shock factor (HSF)-1, to heat shock elements located variably upstream from transcription initiation sites. The stress stimulus responsible for this transcriptional activation is thought to be direct protein damage, including oxidative damage by ROS (1).
Guarana (Paullinia cupana Mart.) protects against amyloid-β toxicity in Caenorhabditis elegans through heat shock protein response activation
Published in Nutritional Neuroscience, 2020
Daniele Coradini Zamberlan, Leticia Priscilla Arantes, Marina Lopes Machado, Tassia Limana da Silveira, Aline Franzen da Silva, Ivana Beatrice Mânica da Cruz, Claudia Pinto Figueiredo, Félix Alexandre Antunes Soares
The expression of chaperones in C. elegans is induced by the heat-shock transcription factor orthologue HSF-1. HSF-1 functions as a transcriptional regulator of stress-induced gene expression whose activity is required for heat-shock and proteotoxicity responses. We performed a paralysis phenotypic analysis in transgenic worms expressing the Aß-peptide using hsf-1 or hsp-16.2 RNAi to confirm whether our GEE treatment influenced the heat shock response. Knocking down hsf-1 in Aß muscle-expressing worms accelerated paralysis. This effect was less pronounced in hsp-16.2 knockdown worms, indicating that HSF-1 function is essential in events of proteotoxicity, presumably by inducing release of the transcriptional target to perform their protein-folding role. Corroborating our data, Walker et al. (2003) reported that hsf-1 (RNAi) worms are thermosensitive, display reduced hsp16-2 expression, and have a reduced life span.34 Furthermore, our data clearly demonstrate that the protective effect of GEE in Aß toxicity is nullified in hsf-1 and hsf-16.2 knockdown worms. These data support our hypothesis that the beneficial effects of GEE occur by activating HSPs. We speculate that GEE induced a hormetic response promoting activation of HSF-1 and inducing transcription of HSPs, which are able to detect unfolded proteins preventing their accumulation and aggregation. Focus on compounds that are efficacious in extending lifespan is substantial to delaying age-associated diseases, since aging affects energy metabolism, proteostasis, and cellular redox control.
Heat shock factor 1 (HSF1)-targeted anticancer therapeutics: overview of current preclinical progress
Published in Expert Opinion on Therapeutic Targets, 2019
Toshiki Kijima, Thomas Prince, Len Neckers, Fumitaka Koga, Yasuhisa Fujii
HSF1-regulated HSR is a transcriptional program providing a normal protein-folding environment and permitting cellular adaptation to proteotoxic stress. However, HSF1 has also been shown to facilitate cancer initiation, maintenance, and progression in numerous cancer cell lines, spontaneous tumorigenesis mouse models, and transplanted xenografts. This adverse effect of HSF1, derived from its original role to enhance the survival of organisms exposed to a harsh environment, suggests a unique therapeutic opportunity. Several preclinical studies have revealed the antitumor activities of small-molecule HSF1 inhibitors. Meanwhile, HSF1 genetic ablation is well tolerated in normal cells and animals under basal physiological conditions. This difference in HSF1 dependence of normal and malignant cells could be exploited as an effective cancer therapeutic strategy.
zHSF1 modulates zper2 expression in zebrafish embryos
Published in Chronobiology International, 2018
Lucas Mennetrier, Tatiana Lopez, Benoist Pruvot, Nadhir Yousfi, Olivier Armant, Hanae Hazhaz, Vincent Lhuissiez, Carmen Garrido, Johanna Chluba
The reaction to temperature changes is regulated by the heat shock response (HSR) that protects cells from damage due to various stressors, including heat. The key factor of the HSR is the transcription factor HSF1. In response to stress, HSF1 trimerizes and activates transcription of heat shock (HS) protein genes and other stress-related genes (Fujimoto and Nakai 2010; Pirkkala et al. 2001). Indeed, the implication of HSF1 in circadian systems was demonstrated in vitro and in vivo by the transcriptional control of the clock gene Period 2 (Per2) (Reinke et al. 2008; Buhr et al. 2010; Tamaru et al. 2011). HSF1 binding regions or elements (HSEs) were found in the upstream region of the Per2 gene in mammals (Kornmann et al. 2007; Reinke et al. 2008; Tamaru et al. 2011).