Heat shock proteins and their role in early mammalian development

Abstract

Elevated body temperature can result from many agents in the natural environment, such as fever, hot weather and heavy exercise. In our modern living conditions additional sources of induced hyperthermia including hot baths, saunas, drugs, electromagnetic radiation and ultrasound have been introduced. Hyperthermia during pregnancy has been shown to cause a wide spectrun of effects in all species studied, including humans, the outcome depending on the dose of heat absorbed by the mother and embryo and the stage of enbryonic or fetal development when exposed. The dose of heat is the product of the elevation of temperature above normal and the duration of the elevation. In relatively uncontrolled natural environmental exposures, embryonic death and resorption or abortion are probably the most common outcome. In less severe exposures (smaller doses) major or minor developmental defects can result and the central nervous system appears to be a major target for its effects. Heat damage to embryos appears to be by apoptotoic and other forms of cell death in organs at critical stages of development. Over many millennia all living orgaisms appear to have developed protective mechanisms against excess heat, known collectively as the heat shock response. This response has been studied intensively over the last 20 years and its mechanisms of protection are now becoming more clearly defined. Exposures to heat (and a number of other toxic agents) trigger the heat shock response which is characterized by abrupt suspension in the normal protein synthesis and the concurrent induction of heat shock genes (hsp) and the synthesis of a set of protein families known collectively as the heat shock proteins (HSP). The hsp are known to be involved in the response in embryos, each has at least two copies, one which appears to have functions in the normal embryonic development (cognate) and another which is induced at a certain dose of heat damage for some time after the initiating dose. Most cognate HSP can normally be found in embryos at all stages of development. At certain critical, early stages of organ formation increased activity of one or more of the hsp families can be identified at the site of the organ analogue. The inducible HSP are usually undetectable during normal development and generally become inducible at these critical inductive stages of organ development, implying a protective function for that process. Excess heat is known to cause denaturation of proteins. Each of the known HSP families appears to protect cells through their chaperone functions in which they bind to adhesive sites on newly synthesized or heat damaged and partially unfolded structural and functional proteins. This prevents the formation of function-less aggregates. The damaged proteins are then either presented for degradation or are reconstituted by orderly disengagement from the chaperone protein. The molecular mechanisms of initiating and regulating the response are now becoming more clearly defined. Trigger mechanisms include release of prostaglandin A1 which can be modulated by glucocorticoids and nonsteroidal anti-inflammatory agents. A heat shock factor (HSF) binds to the heat shock element (hse) on the gene sequence and initiates the hsp response. The signal induction pathway involves mitogen activated proteins (MAP) and stress activated proteins (SAP) which are regulated by phosphorylation. Signals are amplified by kinase cascades while they are being transmitted to the nucleus. Activated MAP and SAP kinases regulate the process by phosphorylation of proteins including transcription factors. HSP, other protein kinases and phosphorylases, growth factor receptors and cytoskeletal proteins. Although this research has defined some pathways indicating how and why heat can cause some defects, a means of preventing them has not yet emerged.