How do cells respond to their thermal environment?

Abstract

Changes in growth temperature induce both activating and inactivating responses from cells, with themagnitude of the temperature change being among the factors that influence which type of responsedominates. Aside from upregulated enzyme activity, induction of thermotolerance is the mostwidely studied and best understood activating response that cells exhibit following heat shock.Inactivating responses to heat shock that are of biomedical interest include heat radiosensitizationand cytotoxicity. Interestingly, the activation energy for inducing thermotolerance, heat cytotoxicity,and radiosensitization all fall within a similar range of 120–146 kcal per mole. The relatively high activationenergy for each of these responses suggests that they all involve a heat-induced molecular transitionas a trigger, and several lines of research suggest strongly that protein denaturation is thecommon transition that triggers all three responses. Low levels of protein denaturation are sufficientto attract the 90 kDa heat shock protein (HSP90) such that it frees up heat shock factor 1, whichthen trimerizes to form an active transcription factor that upregulates expression of heat shock proteins.Upregulation of heat shock proteins and other heat-induced events result in the development of thermotolerance,which protects cells from subsequent exposure to heat shock and other stresses. A moresevere heat shock increases protein denaturation proportionately and leads to aggregation of bothdenatured and native proteins. This results in inactivation of protein synthesis, cell cycle progression,and DNA repair processes such that cells either die or are sensitized to radiation and other cytotoxicevents. The ultimate fate of cells following a heat shock depends upon the summation of the activationand inactivation events that are induced, which appears to be governed by the resultant magnitude ofprotein denaturation and aggregation. Treatments that stabilize cellular proteins against denaturationand aggregation reduce the magnitude of inactivating responses while increasing that of activatingresponses for a given heat shock (time at temperature), while treatments that sensitize proteins todenaturation and aggreation have the converse effect. These findings support the conclusion thatthe determinant of the cellular response to heat shock is the amount of heat-induced proteindenaturation and aggregation and not the time at temperature.