The mechanism whereby heat shock induces apoptosis depends on the innate sensitivity of cells to stress.
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ABSTRACT:
SUBMITTER: Bellmann K
PROVIDER: S-EPMC2866974 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Stem cells in adult organism are responsible for cell turnover and tissue regeneration. The study of stem cell stress response contributes to our knowledge on the mechanisms of damaged tissue repair. Previously, we demonstrated that sublethal heat shock (HS) induced apoptosis in human embryonic stem cells. This study aimed to investigate HS response of human adult stem cells. Human mesenchymal stem cells (MSCs) cultivated in vitro were challenged with sublethal HS. It was found that sublethal HS did not affect the cell viability assessed by annexin V/propidium staining. However, MSCs subjected to severe HS exhibited features of stress-induced premature senescence (SIPS): irreversible cell cycle arrest, altered morphology, increased expression of senescence-associated β-galactosidase (SA-β-gal) activity, and induction of cyclin-dependent kinase inhibitor p21 protein. High level of Hsp70 accumulation induced by sublethal HS did not return to the basal level, at least, after 72 h of the cell recovery when most cells exhibited SIPS hallmarks. MSCs survived sublethal HS, and resumed proliferation sustained the properties of parental MSCs: diploid karyotype, replicative senescence, expression of the cell surface markers, and capacity for multilineage differentiation. Our results showed for the first time that in human MSCs, sublethal HS induced premature senescence rather than apoptosis or necrosis. MSC progeny that survived sublethal HS manifested stem cell properties of the parental cells: limited replicative life span and multilineage capacity.
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Project description:Thymic peptides are immune regulators produced mainly in the thymus. However, thymic peptides such as thymosin-? and thymopoietin have precursors widely expressed outside the thymus, localized in cell nuclei, and involved in vital nuclear functions. In stress-related conditions, they can relocalize. We hypothesized that another thymic peptide, thymulin, could be similarly produced by non-thymic cells during stress and have a precursor therein. Non-thymic cells, including macrophages and fibroblasts, were exposed to oxidative stress, heat, apoptosis, or necrosis. Extracellular thymulin was identified in media of both cell types 2 h after exposure to stress or lethal signals. Therefore, thymulin is released by non-thymic cells. To examine possible thymulin precursors in non-thymic cells, macrophage lysates were analyzed by western blotting. Bands stained with anti-thymulin antibody were detected in two locations, approximately 60 kDa and 10 kDa, which may be a possible precursor and intermediate. All of the exposures except for heat were effective for induction of the 10 kDa protein. BLAST search using thymulin sequence identified SPATS2L, an intranucleolar stress-response protein with molecular weight of 62 kDa, containing thymulin-like sequence. Comparisons of blots stained with anti-thymulin and anti-SPATS2L antibodies indicate that SPATS2L may be a possible candidate for the precursor of thymulin.
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Project description:When the temperature of exponential-phase cultures of Saccharomyces cerevisiae was abruptly raised from 28 to 40 degrees C, trehalose immediately accumulated, whereas the activities of trehalase and trehalose-6-phosphate synthase/trehalose-6-phosphate phosphatase complex increased after a lag period of about 10 min. Heat shock also induced a sudden rise in intracellular glucose, simultaneously with a decrease in the concentration of hexose phosphate and fructose 2,6-bisphosphate. The increase of trehalose-metabolizing enzymes, but not the accumulation of glucose and trehalose, was prevented by cycloheximide. Investigation of the kinetic properties of partially purified enzymes showed that both non-activated and cyclic AMP-dependent-protein-kinase-activated forms of trehalase are almost inactive in the absence of Ca2+ and that the concentration of free Ca2+ required for half-maximal activity increased with increasing temperature, being approx. 1 microM at 30 degrees C and 20 microM at 40 degrees C for the activated form of trehalase. In contrast, trehalose-6-phosphate synthase and trehalose-6-phosphate phosphatase were three times more active at 40 degrees C. It is proposed that the rapid accumulation of trehalose induced by heat shock may be in part explained by changes in the kinetic properties of trehalase and trehalose-6-phosphate synthase/trehalose-6-phosphate phosphatase.
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Project description:Accumulation of misfolded protein in the endoplasmic reticulum (ER) causes stress. The unfolded protein response (UPR), a transcriptional induction pathway, is activated to relieve ER stress. Although UPR is not essential for viability, UPR-deficient cells are more sensitive to ER stress; ire1Delta cells cannot grow when challenged with tunicamycin or by overexpression of misfolded CPY(*). In these cells, multiple functions are defective, including translocation, ER-associated degradation (ERAD), and ER-to-Golgi transport. We tested whether heat shock response (HSR) can relieve ER stress. Using a constitutively active Hsf1 transcription factor to induce HSR without temperature shift, we find that HSR rescues growth of stressed ire1Delta cells, and partially relieves defects in translocation and ERAD. Cargo-specific effects of constitutively active Hsf1 on ER-to-Golgi transport are correlated with enhanced protein levels of the respective cargo receptors. In vivo, HSR is activated by ER stress, albeit to a lower level than that caused by heat. Genomic analysis of HSR targets reveals that >25% have function in common with UPR targets. We propose that HSR can relieve stress in UPR-deficient cells by affecting multiple ER activities.
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Project description:Cancer therapies induce differential cell responses, ranging from efficient cell death to complete stress resistance. The BCL-2 proteins BAX and BAK govern the cellular decision between survival and mitochondrial apoptosis. Therefore, the status of BAX/BAK regulation can predict the cellular apoptosis predisposition. Relative BAX/BAK localization was analyzed in tumor and corresponding non-tumor samples from 34 hepatocellular carcinoma (HCC) patients. Key transcriptome changes and gene expression profiles related to the status of BAX regulation were applied to two independent cohorts including over 500 HCC patients. The prediction of apoptotic response was tested using cell lines and polyclonal tumor isolates. Cellular protection from BAX was confirmed by challenging cells with mitochondrial BAX. We discovered a subgroup of HCC with selective protection from BAX-dependent apoptosis. BAX-protected tumors showed enrichment of signaling pathways associated with oxidative stress response and DNA repair as well as increased genetic heterogeneity. Gene expression profiles characteristic to BAX-specific protection are enriched in poorly differentiated HCCs and show significant association to the overall survival of HCC patients. Consistently, addiction to DNA repair of BAX-protected cancer cells caused selective sensitivity to PARP inhibition. Molecular characteristics of BAX-protected HCC were enriched in cells challenged with mitochondrial BAX. Our results demonstrate that predisposition to BAX activation impairs tumor biology in HCC. Selective BAX inhibition or lack thereof delineates distinct subgroups of HCC patients with molecular features and differential response pattern to apoptotic stimuli and inhibition of DNA repair mechanisms.
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Project description:Caffeine has both positive and negative effects on physiological functions in a dose-dependent manner. C. elegans has been used as an animal model to investigate the effects of caffeine on development. Caffeine treatment at a high dose (30 mM) showed detrimental effects and caused early larval arrest. We performed a comparative proteomic analysis to investigate the mode of action of high-dose caffeine treatment in C. elegans and found that the stress response proteins, heat shock protein (HSP)-4 (endoplasmic reticulum [ER] chaperone), HSP-6 (mitochondrial chaperone), and HSP-16 (cytosolic chaperone), were induced and their expression was regulated at the transcriptional level. These findings suggest that high-dose caffeine intake causes a strong stress response and activates all three stress-response pathways in the worms, including the ER-, mitochondrial-, and cytosolic pathways. RNA interference of each hsp gene or in triple combination retarded growth. In addition, caffeine treatment stimulated a food-avoidance behavior (aversion phenotype), which was enhanced by RNAi depletion of the hsp-4 gene. Therefore, up-regulation of hsp genes after caffeine treatment appeared to be the major responses to alleviate stress and protect against developmental arrest.
| S-EPMC4757805 | biostudies-other
Project description:HspA1A is a cytosolic molecular chaperone essential for cellular homeostasis. HspA1A also localizes at the plasma membrane (PM) of tumor and stressed cells. However, it is currently unknown how this cytosolic protein translocates to the PM. Taking into account that HspA1A interacts with lipids, including phosphatidylserine (PS), and that lipids recruit proteins to the PM, we hypothesized that the interaction of HspA1A with PS allows the chaperone to localize at the PM. To test this hypothesis, we subjected cells to mild heat-shock and the PM-localized HspA1A was quantified using confocal microscopy and cell surface biotinylation. These experiments revealed that HspA1A's membrane localization increased during recovery from non-apoptotic heat-shock. Next, we selectively reduced PS targets by overexpressing the C2 domain of lactadherin (Lact-C2), a known PS-biosensor, and determined that HspA1A's membrane localization was greatly reduced. In contrast, the reduction of PI(4,5)P2 availability by overexpression of the PLCδ-PH biosensor had minimal effects on HspA1A's PM-localization. Implementation of a fluorescent PS analog, TopFluor-PS, established that PS co-localizes with HspA1A. Collectively, these results reveal that HspA1A's PM localization and anchorage depend on its selective interaction with intracellular PS. This discovery institutes PS as a new and dynamic partner in the cellular stress response.
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Project description:It has been hypothesized that human cytomegalovirus (HCMV) could act as a tumor promoter and play an "oncomodulatory" role in the neoplastic process of several human malignancies. However, we demonstrate for the first time that UL138, a HCMV latency-associated gene, could act as a tumor inhibitor in gastric cancer (GC). The expression of UL138 is down-regulated in HCMV positive gastric adenocarcinoma tissues, especially in poorly or none differentiated tumors. Overexpression of UL138 in several human GC cell lines inhibits cell viability and induces apoptosis, in association with the reduction of an anti-apoptotic Bcl-2 protein and the induction of cleaved caspase-3 and caspase-9. Moreover, protein array analysis reveals that UL138 interacts with a chaperone protein, heat shock protein 70 (HSP70). This interaction is confirmed by immunoprecipitation and immunostaining in situ in GC cell lines. In addition, this UL138-mediated cancer cell death could efficiently lead to suppression of human tumor growth in a xenograft animal model of GC. In conclusion, these results uncover a previously unknown role of the cytomegalovirus protein UL138 in inducing GC cells apoptosis, which might imply a general mechanism that viral proteins inhibit cancer growth in interactions with both chaperones and apoptosis-related proteins. Our findings might provide a potential target for new therapeutic strategies of GC treatment.
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Project description:Proteasome inhibitors, such as bortezomib (BTZ), are highly effective and widely used treatments for multiple myeloma. One proposed reason for myeloma cells' exceptional sensitivity to proteasome inhibition is that they produce and continually degrade unusually large amounts of abnormal immunoglobulins. We, therefore, hypothesized that, heat shock may also be especially toxic to myeloma cells by causing protein unfolding, increasing further the substrate load on proteasomes, and, thus, putting further stress on their capacity for protein homeostasis. After a shift from 37 to 43 °C, all four myeloma lines studied underwent extensive apoptosis in 4 h, unlike 13 nonmyeloma cell lines, even though the myeloma cells induced heat-shock proteins and increased protein degradation similar to other cells. Furthermore, two myeloma lines resistant to proteasome inhibitors were also more resistant to 43 °C. Shifting myeloma cells to 43, 41, or 39 °C (which was not cytotoxic) dramatically increased their killing by proteasome inhibitors and inhibitors of ubiquitination or p97/VCP. Combining increased temperature with BTZ increased the accumulation of misfolded proteins and substrate load on the 26S proteasome. The apoptosis seen at 43 °C and at 39 °C with BTZ was mediated by caspase-9 and was linked to an accumulation of the proapoptotic Bcl-2-family member Noxa. Thus, myeloma cells are exceptionally sensitive to increased temperatures, which greatly increase substrate load on the ubiquitin-proteasome system and eventually activate the intrinsic apoptotic pathway. Consequently, for myeloma, mild hyperthermia may be a beneficial approach to enhance the therapeutic efficacy of proteasome inhibitors.
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Project description:Primary cilia are involved in important developmental and disease pathways, such as the regulation of neurogenesis and tumorigenesis. They function as sensory antennae and are essential in the regulation of key extracellular signalling systems. We have investigated the effects of cell stress on primary cilia. Exposure of mammalian cells in vitro, and zebrafish cells in vivo, to elevated temperature resulted in the rapid loss of cilia by resorption. In mammalian cells loss of cilia correlated with a reduction in hedgehog signalling. Heat-shock-dependent loss of cilia was decreased in cells where histone deacetylases (HDACs) were inhibited, suggesting resorption is mediated by the axoneme-localised tubulin deacetylase HDAC6. In thermotolerant cells the rate of ciliary resorption was reduced. This implies a role for molecular chaperones in the maintenance of primary cilia. The cytosolic chaperone Hsp90 localises to the ciliary axoneme and its inhibition resulted in cilia loss. In the cytoplasm of unstressed cells, Hsp90 is known to exist in a complex with HDAC6. Moreover, immediately after heat shock Hsp90 levels were reduced in the remaining cilia. We hypothesise that ciliary resorption serves to attenuate cilia-mediated signalling pathways in response to extracellular stress, and that this mechanism is regulated in part by HDAC6 and Hsp90.
| S-EPMC3516438 | biostudies-literature