scholarly journals Proteotoxic stress of cancer: Implication of the heat-shock response in oncogenesis

2012 ◽  
Vol 227 (8) ◽  
pp. 2982-2987 ◽  
Author(s):  
Chengkai Dai ◽  
Siyuan Dai ◽  
Junyue Cao
Keyword(s):  
Heat Shock ◽  
Heat Shock Response ◽  
Proteotoxic Stress ◽  
Shock Response

scholarly journals The Quinone Methide Aurin Is a Heat Shock Response Inducer That Causes Proteotoxic Stress and Noxa-dependent Apoptosis in Malignant Melanoma Cells

2014 ◽  
Vol 290 (3) ◽  
pp. 1623-1638 ◽  
Author(s):  
Angela L. Davis ◽  
Shuxi Qiao ◽  
Jessica L. Lesson ◽  
Montserrat Rojo de la Vega ◽  
Sophia L. Park ◽  
...  
Keyword(s):  
Heat Shock ◽  
Malignant Melanoma ◽  
Heat Shock Response ◽  
Melanoma Cells ◽  
Quinone Methide ◽  
Proteotoxic Stress ◽  
Shock Response

scholarly journals Depending on the stress, histone deacetylase inhibitors act as heat shock protein co-inducers in motor neurons and potentiate arimoclomol, exerting neuroprotection through multiple mechanisms in ALS models

2020 ◽  
Vol 25 (1) ◽  
pp. 173-191 ◽  
Author(s):  
Rachel Kuta ◽  
Nancy Larochelle ◽  
Mario Fernandez ◽  
Arun Pal ◽  
Sandra Minotti ◽  
...  
Keyword(s):  
Heat Shock ◽  
Histone Deacetylase ◽  
Motor Neurons ◽  
Heat Shock Response ◽  
Hdac Inhibitors ◽  
Dependent Manner ◽  
Hdac Inhibition ◽  
Proteotoxic Stress ◽  
Shock Response ◽  
Stress Dependent

AbstractUpregulation of heat shock proteins (HSPs) is an approach to treatment of neurodegenerative disorders with impaired proteostasis. Many neurons, including motor neurons affected in amyotrophic lateral sclerosis (ALS), are relatively resistant to stress-induced upregulation of HSPs. This study demonstrated that histone deacetylase (HDAC) inhibitors enable the heat shock response in cultured spinal motor neurons, in a stress-dependent manner, and can improve the efficacy of HSP-inducing drugs in murine spinal cord cultures subjected to thermal or proteotoxic stress. The effect of particular HDAC inhibitors differed with the stress paradigm. The HDAC6 (class IIb) inhibitor, tubastatin A, acted as a co-inducer of Hsp70 (HSPA1A) expression with heat shock, but not with proteotoxic stress induced by expression of mutant SOD1 linked to familial ALS. Certain HDAC class I inhibitors (the pan inhibitor, SAHA, or the HDAC1/3 inhibitor, RGFP109) were HSP co-inducers comparable to the hydroxyamine arimoclomol in response to proteotoxic stress, but not thermal stress. Regardless, stress-induced Hsp70 expression could be enhanced by combining an HDAC inhibitor with either arimoclomol or with an HSP90 inhibitor that constitutively induced HSPs. HDAC inhibition failed to induce Hsp70 in motor neurons expressing ALS-linked mutant FUS, in which the heat shock response was suppressed; yet SAHA, RGFP109, and arimoclomol did reduce loss of nuclear FUS, a disease hallmark, and HDAC inhibition rescued the DNA repair response in iPSC-derived motor neurons carrying the FUSP525Lmutation, pointing to multiple mechanisms of neuroprotection by both HDAC inhibiting drugs and arimoclomol.

scholarly journals The amino acid substitution affects cellular response to mistranslation

2021 ◽  
Author(s):  
Matthew D. Berg ◽  
Yanrui Zhu ◽  
Bianca Y. Ruiz ◽  
Raphaël Loll-Krippleber ◽  
Joshua Isaacson ◽  
...  
Keyword(s):  
Amino Acid ◽  
Heat Shock ◽  
Amino Acid Substitution ◽  
Heat Shock Response ◽  
Cellular Response ◽  
Genetic Interactions ◽  
Similar Frequency ◽  
Proteotoxic Stress ◽  
Shock Response ◽  
The Impact

Mistranslation, the mis-incorporation of an amino acid not specified by the standard genetic code, occurs in all organisms. tRNA variants that increase mistranslation arise spontaneously and engineered tRNAs can achieve mistranslation frequencies approaching 10% in yeast and bacteria. Interestingly, human genomes contain tRNA variants with the potential to mistranslate. Cells cope with increased mistranslation through multiple mechanisms, though high levels cause proteotoxic stress. The goal of this study was to compare the genetic interactions and the impact on transcriptome and cellular growth of two tRNA variants that mistranslate at a similar frequency but create different amino acid substitutions in Saccharomyces cerevisiae. One tRNA variant inserts alanine at proline codons whereas the other inserts serine for arginine. Both tRNAs decreased growth rate, with the effect being greater for arginine to serine than for proline to alanine. The tRNA that substituted serine for arginine resulted in a heat shock response. In contrast, heat shock response was minimal for proline to alanine substitution. Further demonstrating the significance of the amino acid substitution, transcriptome analysis identified unique up- and downregulated genes in response to each mistranslating tRNA. Number and extent of negative synthetic genetic interactions also differed depending upon type of mistranslation. Based on the unique responses observed for these mistranslating tRNAs, we predict that the potential of mistranslation to exacerbate diseases caused by proteotoxic stress depends on the tRNA variant. Furthermore, based on their unique transcriptomes and genetic interactions, different naturally occurring mistranslating tRNAs have the potential to negatively influence specific diseases.

scholarly journals The amino acid substitution affects cellular response to mistranslation

2021 ◽  
Author(s):  
Matthew D Berg ◽  
Yanrui Zhu ◽  
Bianca Y Ruiz ◽  
Raphaël Loll-Krippleber ◽  
Joshua Isaacson ◽  
...  
Keyword(s):  
Amino Acid ◽  
Heat Shock ◽  
Amino Acid Substitution ◽  
Heat Shock Response ◽  
Cellular Response ◽  
Genetic Interactions ◽  
Similar Frequency ◽  
Proteotoxic Stress ◽  
Shock Response ◽  
The Impact

Abstract Mistranslation, the mis-incorporation of an amino acid not specified by the “standard” genetic code, occurs in all organisms. tRNA variants that increase mistranslation arise spontaneously and engineered tRNAs can achieve mistranslation frequencies approaching 10% in yeast and bacteria. Interestingly, human genomes contain tRNA variants with the potential to mistranslate. Cells cope with increased mistranslation through multiple mechanisms, though high levels cause proteotoxic stress. The goal of this study was to compare the genetic interactions and the impact on transcriptome and cellular growth of two tRNA variants that mistranslate at a similar frequency but create different amino acid substitutions in Saccharomyces cerevisiae. One tRNA variant inserts alanine at proline codons whereas the other inserts serine for arginine. Both tRNAs decreased growth rate, with the effect being greater for arginine to serine than for proline to alanine. The tRNA that substituted serine for arginine resulted in a heat shock response. In contrast, heat shock response was minimal for proline to alanine substitution. Further demonstrating the significance of the amino acid substitution, transcriptome analysis identified unique up- and downregulated genes in response to each mistranslating tRNA. Number and extent of negative synthetic genetic interactions also differed depending upon type of mistranslation. Based on the unique responses observed for these mistranslating tRNAs, we predict that the potential of mistranslation to exacerbate diseases caused by proteotoxic stress depends on the tRNA variant. Furthermore, based on their unique transcriptomes and genetic interactions, different naturally occurring mistranslating tRNAs have the potential to negatively influence specific diseases.

scholarly journals Quantification of Hsp90 availability reveals differential coupling to the heat shock response

2018 ◽  
Vol 217 (11) ◽  
pp. 3809-3816 ◽  
Author(s):  
Brian D. Alford ◽  
Onn Brandman
Keyword(s):  
Heat Shock ◽  
Heat Shock Response ◽  
Protein Quality ◽  
Multiple Stressors ◽  
Stress Conditions ◽  
Proteotoxic Stress ◽  
Shock Response ◽  
Hsp90 Chaperone ◽  
Differential Coupling ◽  
Expression Program

The heat shock response (HSR) is a protective gene expression program that is activated by conditions that cause proteotoxic stress. While it has been suggested that the availability of free chaperones regulates the HSR, chaperone availability and the HSR have never been precisely quantified in tandem under stress conditions. Thus, how the availability of chaperones changes in stress conditions and the extent to which these changes drive the HSR are unknown. In this study, we quantified Hsp90 chaperone availability and the HSR under multiple stressors. We show that Hsp90-dependent and -independent pathways both regulate the HSR, and the contribution of each pathway varies greatly depending on the stressor. Moreover, stressors that regulate the HSR independently of Hsp90 availability do so through the Hsp70 chaperone. Thus, the HSR responds to diverse defects in protein quality by monitoring the state of multiple chaperone systems independently.

scholarly journals Efficient Heat Shock Response Affects Hyperthermia-Induced Radiosensitization in a Tumor Spheroid Control Probability Assay

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3168
Author(s):  
Oleg Chen ◽  
Soňa Michlíková ◽  
Lisa Eckhardt ◽  
Marit Wondrak ◽  
Adriana M. De Mendoza ◽  
...  
Keyword(s):  
Stress Response ◽  
Heat Shock ◽  
Heat Shock Response ◽  
Cellular Stress Response ◽  
Proteotoxic Stress ◽  
Shock Response ◽  
Pre Treatment ◽  
Shock Proteins ◽  
The Impact

Hyperthermia (HT) combined with irradiation is a well-known concept to improve the curative potential of radiotherapy. Technological progress has opened new avenues for thermoradiotherapy, even for recurrent head and neck squamous cell carcinomas (HNSCC). Preclinical evaluation of the curative radiosensitizing potential of various HT regimens remains ethically, economically, and technically challenging. One key objective of our study was to refine an advanced 3-D assay setup for HT + RT research and treatment testing. For the first time, HT-induced radiosensitization was systematically examined in two differently radioresponsive HNSCC spheroid models using the unique in vitro “curative” analytical endpoint of spheroid control probability. We further investigated the cellular stress response mechanisms underlying the HT-related radiosensitization process with the aim to unravel the impact of HT-induced proteotoxic stress on the overall radioresponse. HT disrupted the proteome’s thermal stability, causing severe proteotoxic stress. It strongly enhanced radiation efficacy and affected paramount survival and stress response signaling networks. Transcriptomics, q-PCR, and western blotting data revealed that HT + RT co-treatment critically triggers the heat shock response (HSR). Pre-treatment with chemical chaperones intensified the radiosensitizing effect, thereby suppressing HT-induced Hsp27 expression. Our data suggest that HT-induced radiosensitization is adversely affected by the proteotoxic stress response. Hence, we propose the inhibition of particular heat shock proteins as a targeting strategy to improve the outcome of combinatorial HT + RT.

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