Molecular biology of thermoregulation.

Our ability to thermoregulate is a key physiological characteristic of humans and all other mammals. Therefore, exploring the physiological mechanisms underlying thermoregulation has been the focus of substantial scientific investigation for a number of years. Studies have ranged from those assessing the ability of humans to tolerate heat and cold stress in occupational, military, and recreational situations to the pathophysiology of heat and cold injuries. Certainly, in the clinical setting, it is widely recognized that fever is an important physiological response to systemic diseases and that body temperature manipulation can be used therapeutically. Other studies in the area of comparative physiology have examined unique conditions of thermoregulation, such as hibernation. Although extensive knowledge exists from whole body, tissue and cellular studies, the application of molecular techniques holds great promise in unraveling the mysteries of physiological responses to heat and cold stress. For example, recent studies have demonstrated that cells from virtually all organisms respond to heat stress by the rapid synthesis of a highly conserved set of polypeptides termed heat shock proteins (HSPs). The precise function of HSPs remains unknown, but there is considerable evidence that these stress proteins are essential for survival at both normal and elevated temperatures. Far less is known about the molecular response(s) to cold stress, but perhaps lessons could be learned from comparative studies of hibernating mammals. This Highlighted Topics series focuses on the molecular biology of thermoregulation, featuring articles that encompass the breadth of gene expression, protein regulation, cytoprotection, cellular signaling, and metabolic regulation that underlie thermoregulatory physiology. In the first mini-review of this Highlighted Topics series, entitled “Effects of heat and cold stress on mammalian gene expression,” Dr. Larry Sonna and colleagues explore changes in gene expression induced by heat and cold stress. Cellular responses to heat stress have been extensively studied and are known to involve both changes in the activities of existing proteins as well as changes in gene expression, most notably expression of HSPs. Until recently, few genes other than those regulating expression of HSPs and chaperones had been shown to undergo heat-induced changes in expression (as defined by level of cellular mRNA). However, recent studies that used gene chip array technologies have made it apparent that the genomic response to heat stress is as complex as the proteomic response and involves changes in expression of genes in every major functional class previously identified as playing a role in the cellular response to heat. A growing body of literature also indicates that cells are capable of mounting a genomic response to cold stress. However, to date, relatively few genes have been clearly identified as responding to cold stress. In this respect, gene chip array studies may help identify candidate genes for further study. Also in this issue is a mini-review entitled “Interplay between molecular chaperones and signaling pathways in survival of heat shock,” by Drs. Vladimir Gabai and Michael Sherman. Exposure of mammalian cells to heat shock activates a number of signaling pathways. Some of these pathways are involved in cell survival, e.g., induction of molecular chaperones (HSP72, HSP27, and others), activation of extracellular-regulated protein kinase (ERK) and protein kinase B (also known as Akt), and phosphorylation of HSP27. On the other hand, heat shock also activates a stress kinase, c-Jun NH2-terminal protein kinase (JNK), which triggers both apoptotic and nonapoptotic cell death. Recent data indicate that HSP72 and HSP27 can also modulate both cell death and survival pathways, via their function as molecular chaperones in refolding of stressdamaged proteins. In the May issue, a mini-review entitled “Heat shock proteins: modifying factors in physiological stress responses and acquired thermotolerance,” by Dr. Kevin C. Kregel will explore the factors that modify HSPs. Recent data show that HSPs play a critical role in the development of thermotolerance and protection from cellular damage associated with stresses such as ischemia, cytokines, and energy depletion. These observations suggest that HSPs are important in both normal cellular homeostasis and the stress response. This mini-review examines recent evidence and hypotheses, suggesting that the HSPs may be important modifying factors in cellular responses to a variety of physiologically relevant conditions such as exercise, hyperthermia, oxidative stress, metabolic challenge, and aging. Also in May, a mini-review entitled “Uncoupling proteins and thermoregulation,” by Drs. George Argyropoulos and Mary Ellen Harper, will examine current data and hypotheses concerning the role of uncoupling proteins (UCP1–5) in thermoregulation and energy balance. Many publications over the past three years have excited the scientific community and raised important new questions about uncoupling, proton leak, and mitochondrial biogenesis. This mini-review exJ Appl Physiol 92: 1365–1366, 2002; 10.1152/japplphysiol.00003.2002.