Redox Factor-1 (Ref-1) Mediates the Activation of AP-1 in HeLa and NIH 3T3 Cells in Response to Heat Shock

Despite well‐studied clinical manifestations, intracellular mechanisms of prolonged hyperthermic injury remain unclear, especially in skeletal muscle. Given muscle's large potential to impact systemic inflammation and metabolism, the response of muscle cells to heat‐mediated injury warrants further investigation. We have previously reported increased activation of NF‐κB signaling and increased NF‐κB and AP‐1‐driven transcripts in oxidative skeletal muscle following 12 h of heat stress. The purpose of this investigation was to examine early heat stress‐induced inflammatory signaling in skeletal muscle. We hypothesized that heat stress would increase NF‐κB and AP‐1 signaling in oxidative skeletal muscle. To address this hypothesis, 32 gilts were randomly assigned to one of four treatment groups (n = 8/group): control (0 h: 21°C) or exposed to heat stress conditions (37°C) for 2 h (n = 8), 4 h (n = 8), or 6 h (n = 8). Immediately following environmental exposure pigs were euthanized and the red portion of the semitendinosus muscle (STR) was harvested. We found evidence of NF‐κB pathway activation as indicated by increased protein abundance of NF‐κB activator IKK‐α following 4 h and increased total NF‐κB protein abundance following 6 h of heat stress. Heat stress also stimulated AP‐1 signaling as AP‐1 protein abundance was increased in nuclear fractions following 4 h of heat stress. Interleukin‐6 protein abundance and activation of the JAK/STAT pathway were decreased in heat stressed muscle. These data indicate that heat stress activated inflammatory signaling in the porcine STR muscle via the AP‐1 pathway and early activation of the NF‐κB pathway.

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“…2013b) and AP‐1 protein abundance was increased by 15 (Diamond et al. 1999) and 30 min (Welc et al. 2013a) of hyperthermia.…”

Section: Discussionmentioning

confidence: 99%

Acute heat stress activated inflammatory signaling in porcine oxidative skeletal muscle

et al. 2017

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“…Heat shock-induced phosphorylation of c-jun by JNK has been demonstrated in mouse 3T3 cells (1), and this was accompanied by an increase in AP-1-specific binding to DNA (1). Interestingly, immunodepletion of the multifunctional DNA repair enzyme and redox sensor Ref-1 (redox factor-1, also known as APE-1) prevented heat shock-induced binding of AP-1 to its consensus sequence (24). This activity was restored by reintroduction of reduced but not oxidized Ref- 1 (24), suggesting that cellular redox state, as sensed by Ref-1, may strongly affect AP-1-mediated gene expression after heat stress in some systems.…”

Section: Changes In Expression Of Other Genes As a Results Of Heat Stressmentioning

confidence: 99%

“…This suggests that downregulation of myc is important to recovery from heat shock. Other changes in transcription factors that are likely of physiological importance include increased expression and activation of p53 by heat shock, which leads to increased expression of cell cycle regulator p21/WAF-1 (79) and to cell cycle arrest (78); activation of AP-1, which affects the expression of many cellular genes involved in stress responses (24); and increased expression of transcription factor egr-1, which also affects cell stress responses and is involved in cell proliferation and differentiation (63).…”

Section: Changes In Expression Of Other Genes As a Results Of Heat Stressmentioning

confidence: 99%

“…We excluded genes whose change in expression has been identified only by genomic or proteomic techniques. Transcriptional systems that show heat-induced changes in expression include 1) the AP-1 system, in which expression of the mRNA (2,8,24) and protein (24) of the two key components ( fos and jun) have been found to be increased by heat shock; 2) c-myc (2,6,8,108), which is downregulated by heat stress through enhanced degradation of cytoplasmic mRNA (108); 3) egr-1, whose heat-induced increased expression in mouse NIH/3T3 fibroblasts is thought to be mediated, in analogy with arsenite-induced cell stress, by p38-and JNK-mediated phosphorylation of transcription factor elk-1 (63); and 4) C/EBP-␣ and C/EBP-␤, whose changes in expression and DNA binding activity as a result of heat shock appear to involve both a change in mRNA expression and a shift in the relative expression of different protein isoforms (120), perhaps by alternative splicing.…”

Section: Changes In Expression Of Other Genes As a Results Of Heat Stressmentioning

confidence: 99%

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Invited Review: Effects of heat and cold stress on mammalian gene expression

Sonna

Fujita

Gaffin

et al. 2002

Journal of Applied Physiology

553

409

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This review examines the effects of thermal stress on gene expression, with special emphasis on changes in the expression of genes other than heat shock proteins (HSPs). There are ∼50 genes not traditionally considered to be HSPs that have been shown, by conventional techniques, to change expression as a result of heat stress, and there are <20 genes (including HSPs) that have been shown to be affected by cold. These numbers will likely become much larger as gene chip array and proteomic technologies are applied to the study of the cell stress response. Several mechanisms have been identified by which gene expression may be altered by heat and cold stress. The similarities and differences between the cellular responses to heat and cold may yield key insights into how cells, and by extension tissues and organisms, survive and adapt to stress.

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“…The redox activity of Ref-1 is regulated by chemical reduction and oxidation in vitro (8,46,47) and may involve Cys-65 and Cys-93 in the NH 2 -terminal region of the protein (43). In cultured cells, Ref-1 serves as an intermediary between thioredoxin and AP-1 in response to oxidant stress induced by PMA (19) or ionizing radiation (44) and mediates AP-1 activation by heat shock (8). However, whether Ref-1 is involved in redox regulation of cell proliferation either in SMCs or in other types of cells is currently unknown.…”

mentioning

confidence: 99%

Redox factor-1 contributes to the regulation of progression from G₀/G₁ to S by PDGF in vascular smooth muscle cells

He¹,

Weintraub²,

Goswami³

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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Redox Factor-1 (Ref-1) Mediates the Activation of AP-1 in HeLa and NIH 3T3 Cells in Response to Heat Shock

Cited by 54 publications

References 39 publications

Acute heat stress activated inflammatory signaling in porcine oxidative skeletal muscle

Acute heat stress activated inflammatory signaling in porcine oxidative skeletal muscle

Invited Review: Effects of heat and cold stress on mammalian gene expression

Redox factor-1 contributes to the regulation of progression from G₀/G₁ to S by PDGF in vascular smooth muscle cells

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Redox Factor-1 (Ref-1) Mediates the Activation of AP-1 in HeLa and NIH 3T3 Cells in Response to Heat Shock

Cited by 54 publications

References 39 publications

Acute heat stress activated inflammatory signaling in porcine oxidative skeletal muscle

Acute heat stress activated inflammatory signaling in porcine oxidative skeletal muscle

Invited Review: Effects of heat and cold stress on mammalian gene expression

Redox factor-1 contributes to the regulation of progression from G0/G1 to S by PDGF in vascular smooth muscle cells

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Redox factor-1 contributes to the regulation of progression from G₀/G₁ to S by PDGF in vascular smooth muscle cells