Correction: Cellular Stress Response Gene Expression During Upper and Lower Body High Intensity Exercises

The stress response gene DDR48 has been characterized in Saccharomyces cerevisiae and Candida albicans to be involved in combating various cellular stressors, from oxidative agents to antifungal compounds. Surprisingly, the biological function of DDR48 has yet to be identified, though it is likely an important part of the stress response. To gain insight into its function, we characterized DDR48 in the dimorphic fungal pathogen Histoplasma capsulatum. Transcriptional analyses showed preferential expression of DDR48 in the mycelial phase. Induction of DDR48 in Histoplasma yeasts developed after treatment with various cellular stress compounds. We generated a ddr48∆ deletion mutant to further characterize DDR48 function. Loss of DDR48 alters the transcriptional profile of the oxidative stress response and membrane synthesis pathways. Treatment with ROS or antifungal compounds reduced survival of ddr48∆ yeasts compared to controls, consistent with an aberrant cellular stress response. In addition, we infected RAW 264.7 macrophages with DDR48-expressing and ddr48∆ yeasts and observed a 50% decrease in recovery of ddr48∆ yeasts compared to wild-type yeasts. Loss of DDR48 function results in numerous negative effects in Histoplasma yeasts, highlighting its role as a key player in the global sensing and response to cellular stress by fungi.

Download Full-text

Age-dependent stress response DNA demethylation and gene upregulation accompany nuclear and skeletal muscle remodeling following acute resistance-type exercise in rats

FACETS ◽

10.1139/facets-2019-0060 ◽

2020 ◽

Vol 5 (1) ◽

pp. 455-473

Author(s):

Erik P. Rader ◽

Brent A. Baker

Keyword(s):

Gene Expression ◽

Stress Response ◽

Differentially Expressed Genes ◽

High Intensity ◽

Dna Demethylation ◽

Differentially Expressed ◽

Response Gene ◽

Old Rats ◽

Muscle Remodeling ◽

Stress Response Gene

Efficacy of high-intensity resistance exercise becomes progressively compromised with aging. Previously, to investigate this, we developed a rodent model of high-intensity training consisting of stretch-shortening contractions (SSCs) and determined that following one month of training, young rats exhibit a robust stress response and 20% performance increase, whereas old rats display a muted stress response and 30% performance decrease. Whether these age-specific responses occur early in training and constitute primary factors in adaptation/maladaptation was not addressed. The aim of the present study was to characterize performance, remodeling, and stress response transcriptional profile 6–120 h following acute SSC exposure. For young rats, the stress response pathway was highly regulated (≥20 differentially expressed genes at each time point) and was accompanied by robust DNA demethylation, tissue remodeling, and isometric torque recovery. For old rats, a muted transcriptional profile (13 and 2 differentially expressed genes at 6 and 120 h, respectively) coincided with deficiencies in demethylation, muscle remodeling, and torque recovery. These findings occurred in the context of heightened chronic levels of stress response gene expression with aging. This demonstrates that age-related constitutive elevations in stress response gene expression was accompanied by diminished SSC-induced responsiveness in epigenomic regulation and tissue remodeling.

Download Full-text

Deuterium Oxide (D2O) Induces Early Stress Response Gene Expression and Impairs Growth and Metastasis of Experimental Malignant Melanoma

Cancers ◽

10.3390/cancers13040605 ◽

2021 ◽

Vol 13 (4) ◽

pp. 605

Author(s):

Jana Jandova ◽

Anh B. Hua ◽

Jocelyn Fimbres ◽

Georg T. Wondrak

Keyword(s):

Gene Expression ◽

Stress Response ◽

Malignant Melanoma ◽

Tumor Growth ◽

Deuterium Oxide ◽

Human Melanoma ◽

Pharmacological Intervention ◽

Melanoma Metastasis ◽

Response Gene ◽

Stress Response Gene

There are two stable isotopes of hydrogen, protium (1H) and deuterium (2H; D). Cellular stress response dysregulation in cancer represents both a major pathological driving force and a promising therapeutic target, but the molecular consequences and potential therapeutic impact of deuterium (2H)-stress on cancer cells remain largely unexplored. We have examined the anti-proliferative and apoptogenic effects of deuterium oxide (D2O; ‘heavy water’) together with stress response gene expression profiling in panels of malignant melanoma (A375V600E, A375NRAS, G361, LOX-IMVI), and pancreatic ductal adenocarcinoma (PANC-1, Capan-2, or MIA PaCa-2) cells with inclusion of human diploid Hs27 skin fibroblasts. Moreover, we have examined the efficacy of D2O-based pharmacological intervention in murine models of human melanoma tumor growth and metastasis. D2O-induction of apoptosis was substantiated by AV-PI flow cytometry, immunodetection of PARP-1, and pro-caspase 3 cleavage, and rescue by pan-caspase inhibition. Differential array analysis revealed early modulation of stress response gene expression in both A375 melanoma and PANC-1 adenocarcinoma cells elicited by D2O (90%; ≤6 h) (upregulated: CDKN1A, DDIT3, EGR1, GADD45A, HMOX1, NFKBIA, or SOD2 (up to 9-fold; p < 0.01)) confirmed by independent RT-qPCR analysis. Immunoblot analysis revealed rapid onset of D2O-induced stress response phospho-protein activation (p-ERK, p-JNK, p-eIF2α, or p-H2AX) or attenuation (p-AKT). Feasibility of D2O-based chemotherapeutic intervention (drinking water (30% w/w)) was demonstrated in a severe combined immunodeficiency (SCID) mouse melanoma metastasis model using luciferase-expressing A375-Luc2 cells. Lung tumor burden (visualized by bioluminescence imaging) was attenuated by D2O, and inhibition of invasiveness was also confirmed in an in vitro Matrigel transwell invasion assay. D2O supplementation also suppressed tumor growth in a murine xenograft model of human melanoma, and median survival was significantly increased without causing adverse effects. These data demonstrate for the first time that systemic D2O administration impairs growth and metastasis of malignant melanoma through the pharmacological induction of deuterium (2H)-stress.

Download Full-text

Solar simulated ultraviolet radiation inactivates HCoV-NL63 and SARS-CoV-2 coronaviruses at environmentally relevant doses

10.1101/2021.06.25.449831 ◽

2021 ◽

Author(s):

Georg T. Wondrak ◽

Jana Jandova ◽

Spencer J. Williams ◽

Dominik Schenten

Keyword(s):

Gene Expression ◽

Stress Response ◽

Uv Light ◽

Gene Expression Array ◽

Array Analysis ◽

Expression Array ◽

Response Gene ◽

Full Spectrum ◽

Solar Uv ◽

Stress Response Gene

The germicidal properties of short wavelength ultraviolet C (UVC) light are well established and used to inactivate many viruses and other microbes. However, much less is known about germicidal effects of terrestrial solar UV light, confined exclusively to wavelengths in the UVA and UVB regions. Here, we have explored the sensitivity of the human coronaviruses HCoV-NL63 and SARS-CoV-2 to solar-simulated full spectrum ultraviolet light (sUV) delivered at environmentally relevant doses. First, HCoV-NL63 coronavirus inactivation by sUV-exposure was confirmed employing (i) viral plaque assays, (ii) RT-qPCR detection of viral genome replication, and (iii) infection-induced stress response gene expression array analysis. Next, a detailed dose-response relationship of SARS-CoV-2 coronavirus inactivation by sUV was elucidated, suggesting a half maximal suppression of viral infectivity at low sUV doses. Likewise, extended sUV exposure of SARS-CoV-2 blocked cellular infection as revealed by plaque assay and stress response gene expression array analysis. Moreover, comparative (HCoV-NL63 versus SARS-CoV-2) single gene expression analysis by RT-qPCR confirmed that sUV exposure blocks coronavirus-induced redox, inflammatory, and proteotoxic stress responses. Based on our findings, we estimate that solar ground level full spectrum UV light impairs coronavirus infectivity at environmentally relevant doses. Given the urgency and global scale of the unfolding SARS-CoV-2 pandemic, these prototype data suggest feasibility of solar UV-induced viral inactivation, an observation deserving further molecular exploration in more relevant exposure models.

Download Full-text

Ezrin Inhibition Up-regulates Stress Response Gene Expression

Journal of Biological Chemistry ◽

10.1074/jbc.m116.718189 ◽

2016 ◽

Vol 291 (25) ◽

pp. 13257-13270 ◽

Cited By ~ 18

Author(s):

Haydar Çelik ◽

Gülay Bulut ◽

Jenny Han ◽

Garrett T. Graham ◽

Tsion Z. Minas ◽

...

Keyword(s):

Gene Expression ◽

Stress Response ◽

Response Gene ◽

Stress Response Gene

Download Full-text

Inflammation, signaling, DNA repair and stress response gene expression during placental development

Journal of Reproductive Immunology ◽

10.1016/j.jri.2006.08.043 ◽

2006 ◽

Vol 71 (2) ◽

pp. 159 ◽

Cited By ~ 1

Author(s):

M. Meller ◽

D. Abetew ◽

C. Qiu ◽

S. Vadachkoria ◽

D. Luthy ◽

...

Keyword(s):

Gene Expression ◽

Dna Repair ◽

Stress Response ◽

Placental Development ◽

Response Gene ◽

Stress Response Gene

Download Full-text

Endogenous rRNA Sequence Variation Can Regulate Stress Response Gene Expression and Phenotype

Cell Reports ◽

10.1016/j.celrep.2018.08.093 ◽

2018 ◽

Vol 25 (1) ◽

pp. 236-248.e6 ◽

Cited By ~ 29

Author(s):

Chad M. Kurylo ◽

Matthew M. Parks ◽

Manuel F. Juette ◽

Boris Zinshteyn ◽

Roger B. Altman ◽

...

Keyword(s):

Gene Expression ◽

Stress Response ◽

Sequence Variation ◽

Rrna Sequence ◽

Response Gene ◽

Stress Response Gene

Download Full-text

Abstract 211: ATF6 and the Adaptive ER Stress Response Enhances Proliferation and Viability in Mouse Cardiac Stem Cells

Circulation Research ◽

10.1161/res.119.suppl_1.211 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Winston T Stauffer ◽

Shirin Doroudgar ◽

Haley N Stephens ◽

Brandi Bailey ◽

Christopher C Glembotski

Keyword(s):

Gene Expression ◽

Stem Cells ◽

Stress Response ◽

Er Stress ◽

Ischemic Heart ◽

Cardiac Stem Cells ◽

Response Gene ◽

Er Stress Response ◽

Chemical Inhibition ◽

Stress Response Gene

Rationale: Cardiac stem cells (CSCs) are beneficial when administered to infarcted mouse or rat hearts. Though the mechanism of these benefits is unknown, CSC vitality likely plays a major role. Thus, investigating the factors governing CSC survival in the ischemic heart may lead to more effective therapeutic strategies. Our previous studies showed that misfolded proteins accumulate in the sarco/endoplasmic reticulum (SR/ER) of the ischemic heart. The transcription factor, ATF6, is a key component of the adaptive ER stress response because it induces genes that reduce the accumulation of misfolded proteins, improving myocyte survival during ischemic stress. While our lab has shown that, in cardiac myocytes, ATF6 is cardioprotective in the ischemic heart, neither the ER stress response nor ATF6 have been examined in CSCs. We hypothesize that ATF6 and the adaptive ER stress response are critical for optimal survival of CSCs. Objective/Methods: To gauge the relevance of the ER stress response in CSCs, we used MTT assays to compare the viabilities of mouse CSCs to neonatal rat ventricular myocytes (NRVM) subjected to treatments that mimic ischemic ER stress in the heart. We also assessed the effect of inhibiting ATF6 on both the ER stress response and CSC viability by using chemical inhibition of ATF6 activation or siRNA-mediated ATF6 knock down. Results: We found that, compared to NRVM, CSCs exhibited lower levels of adaptive ER stress response gene expression and decreased viability in response to ER stress. Thus, relative to NRVM, the adaptive ER stress response is not fully developed in CSCs. We also found that either chemical inhibition of ATF6 activation or ATF6 knock down decreased adaptive ER stress response gene expression. Strikingly, ATF6 inhibition or knockdown decreased CSC viability and cell number by as much as 70%. Conclusions: Thus, compared to cardiac myocytes, CSCs exhibit a reduced adaptive ER stress response and are more sensitive to ER stress, suggesting that enhancement of the ATF6-mediated adaptive ER stress response in CSCs may be a viable therapeutic approach for enhancing stem cell-mediated myocardial repair.

Download Full-text