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 Targeting Cancer Metabolism Breaks Radioresistance by Impairing the Stress Response

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3762
Author(s):  
Melissa Schwab ◽  
Katharina Thunborg ◽  
Omid Azimzadeh ◽  
Christine von Toerne ◽  
Caroline Werner ◽  
...  
Keyword(s):  
Stress Response ◽  
Heat Shock ◽  
Tumor Cells ◽  
Cancer Metabolism ◽  
Glucose Deprivation ◽  
Therapy Resistance ◽  
Hsp70 Expression ◽  
Heat Shock Factor 1 ◽  
Double Knockout ◽  
Ldh Activity

The heightened energetic demand increases lactate dehydrogenase (LDH) activity, the corresponding oncometabolite lactate, expression of heat shock proteins (HSPs) and thereby promotes therapy resistance in many malignant tumor cell types. Therefore, we assessed the coregulation of LDH and the heat shock response with respect to radiation resistance in different tumor cells (B16F10 murine melanoma and LS174T human colorectal adenocarcinoma). The inhibition of LDH activity by oxamate or GNE-140, glucose deprivation and LDHA/B double knockout (LDH−/−) in B16F10 and LS174T cells significantly diminish tumor growth; ROS production and the cytosolic expression of different HSPs, including Hsp90, Hsp70 and Hsp27 concomitant with a reduction of heat shock factor 1 (HSF1)/pHSF1. An altered lipid metabolism mediated by a LDHA/B double knockout results in a decreased presence of the Hsp70-anchoring glycosphingolipid Gb3 on the cell surface of tumor cells, which, in turn, reduces the membrane Hsp70 density and increases the extracellular Hsp70 levels. Vice versa, elevated extracellular lactate/pyruvate concentrations increase the membrane Hsp70 expression in wildtype tumor cells. Functionally, an inhibition of LDH causes a generalized reduction of cytosolic and membrane-bound HSPs in tumor cells and significantly increases the radiosensitivity, which is associated with a G2/M arrest. We demonstrate that targeting of the lactate/pyruvate metabolism breaks the radioresistance by impairing the stress response.

scholarly journals The heat-shock, or HSF1-mediated proteotoxic stress, response in cancer: from proteomic stability to oncogenesis

2017 ◽  
Vol 373 (1738) ◽  
pp. 20160525 ◽  
Author(s):  
Chengkai Dai
Keyword(s):  
Stress Response ◽  
Heat Shock ◽  
Heat Shock Proteins ◽  
Protein Misfolding ◽  
Heat Shock Factor 1 ◽  
Growth And Survival ◽  
Proteotoxic Stress ◽  
Shock Proteins ◽  
Misfolding Diseases

The heat-shock, or HSF1-mediated proteotoxic stress, response (HSR/HPSR) is characterized by induction of heat-shock proteins (HSPs). As molecular chaperones, HSPs facilitate the folding, assembly, transportation and degradation of other proteins. In mammals, heat shock factor 1 (HSF1) is the master regulator of this ancient transcriptional programme. Upon proteotoxic insults, the HSR/HPSR is essential to proteome homeostasis, or proteostasis, thereby resisting stress and antagonizing protein misfolding diseases and ageing. Contrasting with these benefits, an unexpected pro-oncogenic role of the HSR/HPSR is unfolding. Whereas HSF1 remains latent in primary cells without stress, it becomes constitutively activated within malignant cells, rendering them addicted to HSF1 for their growth and survival. Highlighting the HSR/HPSR as an integral component of the oncogenic network, several key pathways governing HSF1 activation by environmental stressors are causally implicated in malignancy. Importantly, HSF1 impacts the cancer proteome systemically. By suppressing tumour-suppressive amyloidogenesis, HSF1 preserves cancer proteostasis to support the malignant state, both providing insight into how HSF1 enables tumorigenesis and suggesting disruption of cancer proteostasis as a therapeutic strategy. This review provides an overview of the role of HSF1 in oncogenesis, mechanisms underlying its constitutive activation within cancer cells and its pro-oncogenic action, as well as potential HSF1-targeting strategies. This article is part of the theme issue ‘Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective’.

L-glutamine Supplementations Enhance Liver Glutamine-Glutathione Axis and Heat Shock Factor-1 Expression in Endurance-Exercise Trained Rats

2015 ◽  
Vol 25 (2) ◽  
pp. 188-197 ◽  
Author(s):  
Éder Ricardo Petry ◽  
Vinicius Fernandes Cruzat ◽  
Thiago Gomes Heck ◽  
Paulo Ivo Homem de Bittencourt ◽  
Julio Tirapegui
Keyword(s):  
Heat Shock ◽  
Wistar Rats ◽  
Redox State ◽  
Hsp70 Expression ◽  
Heat Shock Factor 1 ◽  
Glutathione Disulfide ◽  
Male Wistar Rats ◽  
Shock Proteins ◽  
Transcription Factor 1 ◽  
State Protection

Liver L-glutamine is an important vehicle for the transport of ammonia and intermediary metabolism of amino acids between tissues, particularly under catabolic situations, such as high-intensity exercise. Hence, the aim of this study was to investigate the effects of oral supplementations with L-glutamine in its free or dipeptide forms (with L-alanine) on liver glutamine-glutathione (GSH) axis, and 70 kDa heat shock proteins (HSP70)/heat shock transcription factor 1 (HSF1) expressions. Adult male Wistar rats were 8-week trained (60 min/day, 5 days/week) on a treadmill. During the last 21 days, the animals were daily supplemented with 1 g of L-glutamine/kg body weight per day in either l-alanyl-L-glutamine dipeptide (DIP) form or a solution containing L-glutamine and l-alanine in their free forms (GLN+ALA) or water (controls). Exercise training increased cytosolic and nuclear HSF1 and HSP70 expression, as compared with sedentary animals. However, both DIP and GLN+ALA supplements enhanced HSF1 expression (in both cytosolic and nuclear fractions) in relation to exercised controls. Interestingly, HSF1 rises were not followed by enhanced HSP70 expression. DIP and GLN+ALA supplements increased plasma glutamine concentrations (by 62% and 59%, respectively) and glutamine to glutamate plasma ratio in relation to trained controls. This was in parallel with a decrease in plasma ammonium levels. Supplementations increased liver GSH (by 90%), attenuating the glutathione disulfide (GSSG) to GSH ratio, suggesting a redox state protection. In conclusion, oral administration with DIP and GLN+ALA supplements in endurance-trained rats improve liver glutamine-GSH axis and modulate HSF1 pathway.

scholarly journals Generation of tumors in wing imaginal discs of Drosophila melanogaster third instar larvae to study temporal and spatial patterns of expression of major heat shock proteins

2021 ◽  
Author(s):  
Gunjan Singh ◽  
Subhash C. Lakhotia
Keyword(s):  
Heat Shock ◽  
Heat Shock Proteins ◽  
Cancer Cells ◽  
Spatial Patterns ◽  
Hsp70 Expression ◽  
Loss Of Function ◽  
Temporal And Spatial Patterns ◽  
Early Stages ◽  
Temporal And Spatial ◽  
Shock Proteins

Cancer cells experience a variety of stresses like hypoxia, lack of nutrients, DNA damage and immune responses, which trigger several processes to drive genomic instability and mutation, alterations in gene expression programs, and reprogramming of the metabolic pathways to escape growth inhibition signaling, and acquire resistance to the immune surveillance. Different heat shock proteins are expressed at elevated levels in cancer cells. However, their specific roles in initiation, establishment and progression of cancers are still not clear. Here using the loss of function allele of the apico-basal polarity gene, lgl, we have established models for induction of tumorous somatic clones of different genetic constitutions at defined developmental times for examination of temporal and spatial patterns of expression of the major heat shock protein families, namely Hsp83, Hsp70, Hsp60 and Hsp27. The Hsp83, Hsp60 and Hsp27 begin to express in all cells of the tumor at high levels since early stages (48hr after tumor induction) and continue their high expression at later stages when the tumorous clones accumulate F-actin and get transformed. Levels of the heat shock cognate Hsc70 proteins also follow the same pattern as the other Hsps. However, the major stress-inducible Hsp70 is not expressed at early stages of tumor growth, but expresses at a later stage only in a few cells in a given lgl loss of function clone, which also shows high F-actin aggregates. Thus, the major Hsps, except the Hsp70, seems to be involved in early as well as late stages of epithelial tumors induced by loss of the Lgl cell polarity protein, while the Hsp70 expression in a few cells coincides with their getting transformed. This model will be useful for further genetic studies to dissect specific roles of different Hsps in tumor development and their therapeutic manipulation.

scholarly journals Disaggregases, molecular chaperones that resolubilize protein aggregates

2015 ◽  
Vol 87 (2 suppl) ◽  
pp. 1273-1292 ◽  
Author(s):  
David Z. Mokry ◽  
Josielle Abrahão ◽  
Carlos H.I. Ramos
Keyword(s):  
Heat Shock ◽  
Molecular Chaperones ◽  
Protein Function ◽  
Protein Aggregates ◽  
Cell Physiology ◽  
Biological Processes ◽  
Loss Of Function ◽  
Prion Propagation ◽  
Shock Proteins

The process of folding is a seminal event in the life of a protein, as it is essential for proper protein function and therefore cell physiology. Inappropriate folding, or misfolding, can not only lead to loss of function, but also to the formation of protein aggregates, an insoluble association of polypeptides that harm cell physiology, either by themselves or in the process of formation. Several biological processes have evolved to prevent and eliminate the existence of non-functional and amyloidogenic aggregates, as they are associated with several human pathologies. Molecular chaperones and heat shock proteins are specialized in controlling the quality of the proteins in the cell, specifically by aiding proper folding, and dissolution and clearance of already formed protein aggregates. The latter is a function of disaggregases, mainly represented by the ClpB/Hsp104 subfamily of molecular chaperones, that are ubiquitous in all organisms but, surprisingly, have no orthologs in the cytosol of metazoan cells. This review aims to describe the characteristics of disaggregases and to discuss the function of yeast Hsp104, a disaggregase that is also involved in prion propagation and inheritance.

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.

scholarly journals Expression of heat shock protein 70 is insufficient to extend Drosophila melanogaster longevity

2019 ◽  
Author(s):  
Chengfeng Xiao ◽  
Danna Hull ◽  
Shuang Qiu ◽  
Joanna Yeung ◽  
Jie Zheng ◽  
...  
Keyword(s):  
Heat Treatment ◽  
Drosophila Melanogaster ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Stress Resistance ◽  
Heat Shock Protein 70 ◽  
Biological Effect ◽  
Hsp70 Expression ◽  
Gene Encoding ◽  
Shock Proteins

AbstractIt has been known for over 20 years that Drosophila melanogaster flies with twelve additional copies of the hsp70 gene encoding the 70 kDa heat shock protein lives longer after a non-lethal heat treatment. Since the heat treatment also induces the expression of additional heat shock proteins, the biological effect can be due either to HSP70 acting alone or in combination. This study used the UAS/GAL4 system to determine whether hsp70 is sufficient to affect the longevity and the resistance to thermal, oxidative or desiccation stresses of the whole organism. We observed that HSP70 expression in the nervous system or muscles has no effect on longevity or stress resistance but ubiquitous expression reduces the life span of males. We also observed that the down-regulation of Hsp70 using RNAi did not affect longevity.

Expression of heat shock proteins in medulloblastoma

2013 ◽  
Vol 12 (5) ◽  
pp. 452-457 ◽  
Author(s):  
George A. Alexiou ◽  
George Vartholomatos ◽  
Kalliopi Stefanaki ◽  
Amalia Patereli ◽  
Lefkothea Dova ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Proteins ◽  
Significant Positive Correlation ◽  
Large Cell ◽  
Hsp70 Expression ◽  
Ki 67 ◽  
Positive Correlation ◽  
Wide Range ◽  
Shock Proteins ◽  
Multiplex Bead

Object Medulloblastoma (MB) is the most common malignant brain tumor in children. Heat shock proteins (HSPs) comprise a superfamily of proteins that serve as molecular chaperones and are overexpressed in a wide range of human cancers. The purpose of the present study was to investigate the expression of HSP27 (pSer82), HSP27 (pSer15), HSP40, HSP60, HSP70, HSP90-α, Akt, and phospho-Akt by multiplex bead array assay of MBs. The results of HSP and Akt expression were correlated with MB subtype; immunohistochemical expression of Ki-67 index, bcl-2, and p53; and patients' prognosis. Methods The authors retrospectively evaluated 25 children with MB who underwent surgery. Immunohistochemical analysis of Ki-67, p53, and bcl-2 expression was performed in all cases. By using multiplex bead array assay, a simultaneous detection of HSP27 (pSer82), HSP27 (pSer15), HSP40, HSP60, HSP70, HSP90-α, Akt, and phospho-Akt was performed. Results Medulloblastoma with extensive nodularity had significantly lower HSP27 (pSer15) expression (p = 0.039) but significantly higher HSP60 expression (p = 0.021) than classic MB. Large-cell MB had significantly higher HSP70 expression (p = 0.028) than classic MB. No significant difference was found between HSP27 (pSer82), HSP40, HSP90-α, Akt, or phospho-Akt expression and MB subtype. Large-cell MBs had significantly higher Ki-67 index compared with classic MBs (p = 0.033). When analyzing all MBs, there was a significant negative correlation between HSP27 (pSer15) and Ki-67 index (r = −0.475, p = 0.016); a significant positive correlation between HSP70 expression and Ki-67 index (r = 0.407, p = 0.043); and a significant positive correlation between HSP70 expression and bcl-2 index (r = 0.491, p = 0.023). Patients with large-cell MB had a worse survival than those with classic MB, but the difference did not reach statistical significance (p = 0.076). Conclusions A substantial expression of several HSPs in MB was observed. Given that HSPs represent an attractive strategy for anticancer therapy, further studies, involving larger series of patients, are obviously necessary to clarify the relationship of HSPs with tumor aggressiveness and prognosis.

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