Heat shock protein 90 (HSP90) is a member of a family of molecular chaperone proteins which can be upregulated by various stressors including heat stress leading to increases in HSP90 protein expression. Its primary functions include (1) renaturing and denaturing of damaged proteins caused by heat stress and (2) interacting with client proteins to induce cell signaling for gene expression. The latter function is of interest because, in cancer cells, HSP90 has been reported to interact with the transcription hypoxic-inducible factor 1
Heat shock proteins (HSP’s) are classified as molecular chaperones that play an integral role in the maintenance of damaged cells after heat exposure. When a living organism is exposed to a hyperthermic environment, intracellular HSP expression is increased. A function of HSPs is to sequester and refold denatured proteins [
Heat shock protein 90 (HSP90) is a 90 kda protein that has specific functional characteristics when compared to other members of the HSP family. Along with renaturing damaged proteins, HSP90 interacts with target client proteins stimulating the activation of specific signaling transduction pathways [
In endurance athletics, training methods which involve the use of hypobaric hypoxia have been used to induce an increase in HIF1
The idea that HSP90 interacts with HIF1
The understanding of molecular adaptations to HA may lead to future sports sciences applications. Results from studies using
The purpose of this paper is to discuss the possibility of using HA to induce some of the adaptations that occur with altitude acclimation. We will review
Heat shock protein 90 is ubiquitously expressed [
Heat shock protein 90 is an elongated dimer protein in which the C-termini are connected in the middle of the protein with the N-termini located at distal ends [
Geldanamycin is an HSP90 inhibitor which binds to the active site of HSP90 inhibiting ATP hydrolysis, thus decreasing activation of the protein. When GA is added to HSP90 and denatured luciferase, there is a 50% decrease in protein refolding [
In summary, HSP90 acts to sequester and refold proteins that have been damaged during heat stress. The role of HSP90 to refold denatured proteins is illustrated when there is a decrease in protein refolding and function after inhibition by GA. The results from these studies provide support that HSP90 plays a role in damaged protein rebuilding. Additionally, HSP90 also appears to interact and activate client proteins which can lead to activation of cell signaling pathways. In the next section, HSP90’s role in interacting with client proteins will be discussed.
Along with acting as a molecular chaperone to refold denatured proteins after heat stress, HSP90 also interacts with client proteins [
Studies have shown that HSP90 is capable of binding to steroid receptors [
Heat shock protein 90 interacts with aryl hydrocarbon receptor (AHR) (also known as dioxin receptor). Aryl hydrocarbon receptor is a transcription factor [
Nitric oxide synthase (NOS) is an enzyme that oxidizes L-arginine to citrulline and the by-product of that reaction is nitric oxide (NO) [
Heat shock protein 90 plays a role in the regulation of all three isoforms of NOS (inducible NOS, epithelial NOS, and neuronal NOS) [
Collectively, the results from these investigations illustrate that HSP90 interacts with and can increase activity of NOS. Activation and upregulation of NOS can lead to downstream signal transduction causing vasodilation. Inhibition of HSP90 can attenuate the physiological responses by decreasing the signal transduction to decrease vasodilatory responses.
Vascular growth is mediated by the transcription factor VEGF which is regulated by HIF1
Cancer growth is dependent on an increased vasculature which provides optimal nutrient delivery and blood flow. The upregulation of HSP90 in cancer cells plays a role in mediating cancer growth by inducing increases in HIF1
Hypoxic-inducible factor 1
In normoxia, HIF1
As previously discussed, one function of HSP90 is to interact with and activate client proteins [
The physiological significance of the HSP90-HIF1
At altitude there is a decrease in the PIO2 reducing oxygen delivery to the working muscles which results in decreased exercise performance [
Exercising in a hypoxic environment or severe hypoxic exposure alone can induce molecular adaptations that are mediated by transcription factors that stimulate angiogenesis [
Semenza and colleagues [
The idea that HIF1
Scientific investigations of the response of HSP90 following exercise in humans are scarce. The evidence available suggests that intracellular HSP90 changes very little after exercise [
Heat shock protein 90 is a heat-inducible protein indicating that stress such as heat can cause a greater intracellular protein expression. Mice, exposed to 5 days of continuous heat exposure at 37°C, showed that HSP90 was increased in the spleen, brain, and heart tissues [
The evidence for induction of intracellular HSP90 in leukocytes by exercise stimulus alone is conflicting. Perhaps a combination of exercise and heat may have an additive effect to induce HSP90 expression (Figure
Exercise and heat exposure increases intracellular HSP90. HSP90 precipitates and phosphorylates HIF1
Illustration of the client proteins that HSP90 interacts with and their physiological function.
We speculate that a combination of exercise and heat stress will have a synergistic effect of increasing HSP90 leading to greater HSP90-HIF1
Research suggests that heat exposure both
Evidence from the studies of Katschinski et al. [
The equivocal results from studies investigating HSP90s response to exercise and heat separately and/or together are compounded by different methodology. The use of various
To test this hypothesis, experiments using
We propose that exercise and heat would have effects similar to those of hypoxia. Such a cross-adaptation response would be beneficial to military personnel rapidly deployed to high altitude environments, endurance athletes preparing to compete at altitude, or mountaineers preparing for high altitude expeditions. If HA induces red cell formation and vascular growth in a normoxic environment, it may enhance oxygen-carrying capacity, a limitation to exercise at altitude. Individuals would not have to travel to high altitude terrain or use costly equipment to acclimate to high altitude. Evidence suggests that prior heat exposure may be advantageous to those exercising in hypoxia. Hiestand and colleagues [
The interaction between HSP90 and HIF1
In conclusion, findings from
The authors of this paper declare that they have no conflict of interests.