scholarly journals Molecular Chaperones in Osteosarcoma: Diagnosis and Therapeutic Issues

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 754
Author(s):  
Morgane Lallier ◽  
Louise Marchandet ◽  
Brice Moukengue ◽  
Celine Charrier ◽  
Marc Baud’huin ◽  
...  
Keyword(s):  
Heat Shock ◽  
Molecular Mechanisms ◽  
Therapeutic Targets ◽  
Large Family ◽  
Poor Responders ◽  
Heat Shock Factor 1 ◽  
Primary Bone Tumor ◽  
Apoptosis Inhibition ◽  
Primary Bone ◽  
Shock Proteins

Osteosarcoma (OS) is the most common form of primary bone tumor affecting mainly children and young adults. Despite therapeutic progress, the 5-year survival rate is 70%, but it drops drastically to 30% for poor responders to therapies or for patients with metastases. Identifying new therapeutic targets is thus essential. Heat Shock Proteins (HSPs) are the main effectors of Heat Shock Response (HSR), the expression of which is induced by stressors. HSPs are a large family of proteins involved in the folding and maturation of other proteins in order to maintain proteostasis. HSP overexpression is observed in many cancers, including breast, prostate, colorectal, lung, and ovarian, as well as OS. In this article we reviewed the significant role played by HSPs in molecular mechanisms leading to OS development and progression. HSPs are directly involved in OS cell proliferation, apoptosis inhibition, migration, and drug resistance. We focused on HSP27, HSP60, HSP70 and HSP90 and summarized their potential clinical uses in OS as either biomarkers for diagnosis or therapeutic targets. Finally, based on different types of cancer, we consider the advantage of targeting heat shock factor 1 (HSF1), the major transcriptional regulator of HSPs in OS.

scholarly journals Heat Shock Proteins: Agents of Cancer Development and Therapeutic Targets in Anti-Cancer Therapy

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 60 ◽  
Author(s):  
Chul Won Yun ◽  
Hyung Joo Kim ◽  
Ji Ho Lim ◽  
Sang Hun Lee
Keyword(s):  
Heat Shock ◽  
Cancer Therapy ◽  
Heat Shock Proteins ◽  
Therapeutic Targets ◽  
Large Family ◽  
Therapy Resistance ◽  
Cancer Drug ◽  
Cancer Drug Resistance ◽  
Anti Cancer ◽  
Shock Proteins

Heat shock proteins (HSPs) constitute a large family of molecular chaperones classified by their molecular weights, and they include HSP27, HSP40, HSP60, HSP70, and HSP90. HSPs function in diverse physiological and protective processes to assist in maintaining cellular homeostasis. In particular, HSPs participate in protein folding and maturation processes under diverse stressors such as heat shock, hypoxia, and degradation. Notably, HSPs also play essential roles across cancers as they are implicated in a variety of cancer-related activities such as cell proliferation, metastasis, and anti-cancer drug resistance. In this review, we comprehensively discuss the functions of HSPs in association with cancer initiation, progression, and metastasis and anti-cancer therapy resistance. Moreover, the potential utilization of HSPs to enhance the effects of chemo-, radio-, and immunotherapy is explored. Taken together, HSPs have multiple clinical usages as biomarkers for cancer diagnosis and prognosis as well as the potential therapeutic targets for anti-cancer treatment.

scholarly journals Developmental Expression and Functions of the Small Heat Shock Proteins in Drosophila

2018 ◽  
Vol 19 (11) ◽  
pp. 3441 ◽  
Author(s):  
Teresa Jagla ◽  
Magda Dubińska-Magiera ◽  
Preethi Poovathumkadavil ◽  
Małgorzata Daczewska ◽  
Krzysztof Jagla
Keyword(s):  
Heat Shock ◽  
Heat Shock Proteins ◽  
Large Family ◽  
Active Role ◽  
Stress Conditions ◽  
Developmental Expression ◽  
Shsp Gene ◽  
Time Specific ◽  
Shock Proteins ◽  
And Function

Heat shock proteins (Hsps) form a large family of evolutionarily conserved molecular chaperones that help balance protein folding and protect cells from various stress conditions. However, there is growing evidence that Hsps may also play an active role in developmental processes. Here, we take the example of developmental expression and function of one class of Hsps characterized by low molecular weight, the small Hsps (sHsps). We discuss recent reports and genome-wide datasets that support vital sHsps functions in the developing nervous system, reproductive system, and muscles. This tissue- and time-specific sHsp expression is developmentally regulated, so that the enhancer sequence of an sHsp gene expressed in developing muscle, in addition to stress-inducible elements, also carries binding sites for myogenic regulatory factors. One possible reason for sHsp genes to switch on during development and in non-stress conditions is to protect vital developing organs from environmental insults.

scholarly journals AKT1 mediates multiple phosphorylation events that functionally promote HSF1 activation

2020 ◽  
Author(s):  
Wen-Cheng Lu ◽  
Ramsey Omari ◽  
Haimanti Ray ◽  
Richard L. Carpenter
Keyword(s):  
Heat Shock ◽  
Functional Role ◽  
Transcriptional Activity ◽  
Heat Shock Factor 1 ◽  
Heat Stress Response ◽  
Subsequent Investigation ◽  
Important Regulator ◽  
Shock Proteins ◽  
Hsf1 Gene

AbstractThe heat stress response activates the transcription factor heat shock factor 1 (HSF1), which subsequently upregulates heat shock proteins to maintain the integrity of the proteome. HSF1 activity requires nuclear localization, trimerization, DNA binding, phosphorylation, and gene transactivation. Phosphorylation at S326 is an important regulator of HSF1 transcriptional activity. Phosphorylation at S326 is mediated by AKT1, mTOR, p38, and MEK1. mTOR, p38, and MEK1 all phosphorylated S326 but AKT1 was the more potent activator. Mass spectrometry showed that AKT1 phosphorylated HSF1 at T142, S230, and T527 in addition to S326 whereas the other kinases did not. Subsequent investigation revealed that phosphorylation at T142 is necessary for HSF1 trimerization and that S230, S326, and T527 are required for HSF1 gene transactivation and recruitment of TFIIB and CDK9. This study suggests that HSF1 activity is regulated by phosphorylation at specific residues that promote different stages of HSF1 activation. Furthermore, this is the first study to identify the functional role of these phosphorylation events.

Inhibition of Heat Shock Factor 1 Enhances Repressive Molecular Mechanisms on the POMC Promoter

2019 ◽  
Vol 109 (4) ◽  
pp. 362-373
Author(s):  
Denis Ciato ◽  
Ran Li ◽  
Jose Luis Monteserin Garcia ◽  
Lilia Papst ◽  
Sarah D’Annunzio ◽  
...  
Keyword(s):  
Heat Shock ◽  
Clinical Features ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Primary Cultures ◽  
Heat Shock Protein 90 ◽  
Heat Shock Factor ◽  
Heat Shock Factor 1 ◽  
Promising Treatment ◽  
Acth Secreting

Background: Cushing’s disease (CD) is caused by adrenocorticotropic hormone (ACTH)-secreting pituitary tumours. They express high levels of heat shock protein 90 and heat shock factor 1 (HSF1) in comparison to the normal tissue counterpart, indicating activated cellular stress. Aims: Our objectives were: (1) to correlate HSF1 expression with clinical features and hormonal/radiological findings of CD, and (2) to investigate the effects of HSF1 inhibition as a target for CD treatment. Patients/Methods: We examined the expression of total and pSer326HSF1 (marker for its transcriptional activation) by Western blot on eight human CD tumours and compared to the HSF1 status of normal pituitary. We screened a cohort of 45 patients with CD for HSF1 by immunohistochemistry and correlated the HSF1 immunoreactivity score with the available clinical data. We evaluated the effects of HSF1 silencing with RNA interference and the HSF1 inhibitor KRIBB11 in AtT-20 cells and four primary cultures of human corticotroph tumours. Results: We show that HSF1 protein is highly expressed and transcriptionally active in CD tumours in comparison to normal pituitary. The immunoreactivity score for HSF1 did not correlate with the typical clinical features of the disease. HSF1 inhibition reduced proopiomelanocortin (Pomc) transcription in AtT-20 cells. The HSF1 inhibitor KRIBB11 suppressed ACTH synthesis from 75% of human CD tumours in primary cell culture. This inhibitory action on Pomc transcription was mediated by increased glucocorticoid receptor and suppressed Nurr77/Nurr1 and AP-1 transcriptional activities. Conclusions: These data show that HSF1 regulates POMC transcription. Pharmacological targeting of HSF1 may be a promising treatment option for the control of excess ACTH secretion in CD.

Induced Expression of the Heat Shock Protein Genes uspA and grpE during Starvation at Low Temperatures and Their Influence on Thermal Resistance of Escherichia coli O157:H7

2003 ◽  
Vol 66 (11) ◽  
pp. 2045-2050 ◽  
Author(s):  
YI ZHANG ◽  
MANSEL W. GRIFFITHS
Keyword(s):  
Heat Shock ◽  
Heat Shock Proteins ◽  
Stress Responses ◽  
Thermal Tolerance ◽  
Molecular Mechanisms ◽  
Fluorescent Protein ◽  
Bacterial Cells ◽  
Induced Expression ◽  
Green Fluorescent ◽  
Shock Proteins

Heat shock proteins play an important role in protecting bacterial cells against several stresses, including starvation. In this study, the promoters for two genes encoding heat shock proteins involved in many stress responses, UspA and GrpE, were fused with the green fluorescent protein (gfp) gene. Thus, the expression of the two genes could be quantified by measuring the fluorescence emitted by the cells under different environmental conditions. The heat resistance levels of starved and nonstarved cells during storage at 5, 10, and 37°C were compared with the levels of expression of the uspA and grpE genes. D52-values (times required for decimal reductions in count at 52°C) increased by 11.5, 14.6, and 18.5 min when cells were starved for 3 h at 37°C, for 24 h at 10°C, and for 2 days at 5°C, respectively. In all cases, these increases were significant (P < 0.01), indicating that the stress imposed by starvation altered the ability of E. coli O157:H7 to survive subsequent heat treatments. Thermal tolerance was correlative with the induction of UspA and GrpE. At 5°C, the change in the thermal tolerance of the pathogen was positively linked to the induced expression of the grpE gene but negatively related to the expression of the uspA gene. The results obtained in this study indicate that UspA plays an important role in starvation-induced thermal tolerance at 37°C but that GrpE may be more involved in regulating this response at lower temperatures. An improvement in our understanding of the molecular mechanisms involved in these cross-protection responses may make it possible to devise strategies to limit their effects.

scholarly journals Membrane-Associated Heat Shock Proteins in Oncology: From Basic Research to New Theranostic Targets

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1263 ◽  
Author(s):  
Maxim Shevtsov ◽  
Zsolt Balogi ◽  
William Khachatryan ◽  
Huile Gao ◽  
László Vígh ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Proteins ◽  
Molecular Chaperones ◽  
Intracellular Localization ◽  
Large Family ◽  
Basic Research ◽  
Stress Factors ◽  
Small Hsps ◽  
Stress Oxidative ◽  
Shock Proteins

Heat shock proteins (HSPs) constitute a large family of conserved proteins acting as molecular chaperones that play a key role in intracellular protein homeostasis, regulation of apoptosis, and protection from various stress factors (including hypoxia, thermal stress, oxidative stress). Apart from their intracellular localization, members of different HSP families such as small HSPs, HSP40, HSP60, HSP70 and HSP90 have been found to be localized on the plasma membrane of malignantly transformed cells. In the current article, the role of membrane-associated molecular chaperones in normal and tumor cells is comprehensively reviewed with implications of these proteins as plausible targets for cancer therapy and diagnostics.

scholarly journals Disruption of Heat Shock Factor 1 Reveals an Essential Role in the Ubiquitin Proteolytic Pathway

2000 ◽  
Vol 20 (8) ◽  
pp. 2670-2675 ◽  
Author(s):  
Lila Pirkkala ◽  
Tero-Pekka Alastalo ◽  
XiaoXia Zuo ◽  
Ivor J. Benjamin ◽  
Lea Sistonen
Keyword(s):  
Stress Response ◽  
Heat Shock ◽  
Hsp70 Expression ◽  
Heat Shock Factor 1 ◽  
Loss Of Function ◽  
Down Regulation ◽  
Proteolytic Pathway ◽  
Ubiquitin Proteasome ◽  
A Cell ◽  
Shock Proteins

ABSTRACT Inhibition of proteasome-mediated protein degradation machinery is a potent stress stimulus that causes accumulation of ubiquitinated proteins and increased expression of heat shock proteins (Hsps). Hsps play pivotal roles in homeostasis and protection in a cell, through their well-recognized properties as molecular chaperones. The inducible Hsp expression is regulated by the heat shock transcription factors (HSFs). Among mammalian HSFs, HSF1 has been shown to be important for regulation of the heat-induced stress gene expression, whereas the function of HSF2 in stress response is unclear. Recent reports have suggested that both HSF1 and HSF2 are affected during down-regulation of ubiquitin-proteasome pathway (Y. Kawazoe et al., Eur. J. Biochem. 255:356–362, 1998; A. Mathew et al., Mol. Cell. Biol. 18:5091–5098, 1998; D. Kim et al., Biochem. Biophys. Res. Commun. 254:264–268, 1999). To date, however, no unambiguous evidence has been presented as to whether a single specific HSF or multiple members of the HSF family are required for transcriptional induction of heat shock genes when proteasome activity is down-regulated. Therefore, by using loss-of-function and gain-of-function strategies, we investigated the specific roles of mammalian HSFs in regulation of the ubiquitin-proteasome-mediated stress response. Here we demonstrate that HSF1, but not HSF2, is essential and sufficient for up-regulation of Hsp70 expression during down-regulation of the ubiquitin proteolytic pathway. We propose that specificity of HSF1 could be an important therapeutic target during disease pathogenesis associated with abnormal ubiquitin-dependent proteasome function.

scholarly journals Impact of Exercise and Metabolic Disorders on Heat Shock Proteins and Vascular Inflammation

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Earl G. Noble ◽  
Garry X. Shen
Keyword(s):  
Oxidative Stress ◽  
Heat Shock ◽  
Heat Shock Proteins ◽  
Inflammatory Mediators ◽  
Metabolic Disorders ◽  
Cell Injury ◽  
Vascular Inflammation ◽  
Atherosclerotic Cardiovascular Disease ◽  
Heat Shock Factor 1 ◽  
Shock Proteins

Heat shock proteins (Hsp) play critical roles in the body’s self-defense under a variety of stresses, including heat shock, oxidative stress, radiation, and wounds, through the regulation of folding and functions of relevant cellular proteins. Exercise increases the levels of Hsp through elevated temperature, hormones, calcium fluxes, reactive oxygen species (ROS), or mechanical deformation of tissues. Isotonic contractions and endurance- type activities tend to increase Hsp60 and Hsp70. Eccentric muscle contractions lead to phosphorylation and translocation of Hsp25/27. Exercise-induced transient increases of Hsp inhibit the generation of inflammatory mediators and vascular inflammation. Metabolic disorders (hyperglycemia and dyslipidemia) are associated with type 1 diabetes (an autoimmune disease), type 2 diabetes (the common type of diabetes usually associated with obesity), and atherosclerotic cardiovascular disease. Metabolic disorders activate HSF/Hsp pathway, which was associated with oxidative stress, increased generation of inflammatory mediators, vascular inflammation, and cell injury. Knock down of heat shock factor-1 (HSF1) reduced the activation of key inflammatory mediators in vascular cells. Accumulating lines of evidence suggest that the activation of HSF/Hsp induced by exercise or metabolic disorders may play a dual role in inflammation. The benefits of exercise on inflammation and metabolism depend on the type, intensity, and duration of physical activity.

scholarly journals Molecular mechanisms of heat shock proteins (HSPs) involved in neoplasm development

2019 ◽  
Vol 34 (2) ◽  
pp. 455-474
Author(s):  
Rafael Guerrero-Rojas ◽  
Carlos Guerrero-Fonsecaz
Keyword(s):  
Heat Shock ◽  
Heat Shock Proteins ◽  
Molecular Mechanisms ◽  
Shock Proteins

scholarly journals HSF1Base: A Comprehensive Database of HSF1 (Heat Shock Factor 1) Target Genes

2019 ◽  
Vol 20 (22) ◽  
pp. 5815 ◽  
Author(s):  
Kovács ◽  
Sigmond ◽  
Hotzi ◽  
Bohár ◽  
Fazekas ◽  
...  
Keyword(s):  
Heat Shock ◽  
High Throughput ◽  
Ribosome Biogenesis ◽  
Target Genes ◽  
Enrichment Analysis ◽  
Cell Types ◽  
Heat Shock Factor ◽  
Heat Shock Factor 1 ◽  
Genes Encoding ◽  
Shock Proteins

: HSF1 (heat shock factor 1) is an evolutionarily conserved master transcriptional regulator of the heat shock response (HSR) in eukaryotic cells. In response to high temperatures, HSF1 upregulates genes encoding molecular chaperones, also called heat shock proteins, which assist the refolding or degradation of damaged intracellular proteins. Accumulating evidence reveals however that HSF1 participates in several other physiological and pathological processes such as differentiation, immune response, and multidrug resistance, as well as in ageing, neurodegenerative demise, and cancer. To address how HSF1 controls these processes one should systematically analyze its target genes. Here we present a novel database called HSF1Base (hsf1base.org) that contains a nearly comprehensive list of HSF1 target genes identified so far. The list was obtained by manually curating publications on individual HSF1 targets and analyzing relevant high throughput transcriptomic and chromatin immunoprecipitation data derived from the literature and the Yeastract database. To support the biological relevance of HSF1 targets identified by high throughput methods, we performed an enrichment analysis of (potential) HSF1 targets across different tissues/cell types and organisms. We found that general HSF1 functions (targets are expressed in all tissues/cell types) are mostly related to cellular proteostasis. Furthermore, HSF1 targets that are conserved across various animal taxa operate mostly in cellular stress pathways (e.g., autophagy), chromatin remodeling, ribosome biogenesis, and ageing. Together, these data highlight diverse roles for HSF1, expanding far beyond the HSR.

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