Apoptosis, the heat shock response, hyperthermia, birth defects, disease and cancer. Where are the common links?
Many cells die during normal prenatal development. Throughout postnatal life, production of new cells is balanced by death of older cells to maintain the normal mass of organs and tissues. In these situations, cell death is usually in the form of apoptosis, characterized morphologically by shrinkage of cellular contents within their membranes, condensation and margination of chromatin against the nuclear membrane and phagocytic removal by macrophages or adjacent cells of the organ. It is initiated and controlled by a complex set of gene-directed activities. The process is tidy and avoids the inflammatory effects of degenerating cellular contents on other tissues. The capacity to undergo this form of cell death is lost in neoplastic cell lines. In embryos the normal process of apoptosis has been termed programmed cell death, and in prenatal and mature animals a number of toxic agents can also cause morphologically typical forms of apoptosis. The heat shock (HS) response occurs in a wide range of plants and animals as a basic reaction that assists survival and recovery from the effects of heat and other toxic agents. It appears to be an extension of the cellular mechanism by which newly synthesized proteins are received by other ('chaperone') proteins to be transported within cells and folded into their functional configurations. Chaperone proteins adhere to hydrophobic sites on newly synthesized proteins, preventing the formation of functionless aggregates by random adhesion to hydrophobic sites on other proteins. After disengagement, the new protein can assume its proper configuration. Chaperone proteins are normally present in embryos, the genes encoding for their synthesis becoming activated particularly at inductive and rapid growth stages of organ formation. Hyperthermia and some other toxic agents also activate a set of inducible heat shock genes to synthesize induced HS proteins that adhere to uncovered hydrophobic sites on the heat denatured proteins, preventing random associations and allowing reconstitution or assisting degradation of irreparably damaged proteins. Irreparable damage usually results in a morphologically typical form of apoptotic cell death. Knowledge of signals initiating the response is incomplete but includes prostaglandin release, amplification by kinase cascades of mitogen and stress-activated protein signals, binding of the HS factor to the HS element on the HS gene. Maternal hyperthermia is a proven teratogen in all species studied. The HS response is inducible in early embryonic life but it fails to protect embryos against damage at certain stages of development. An embryo must absorb a threshold 'dose' of heat if defects are to be caused, the dose being the product of the level and the duration of elevation above the normal maternal temperature. The lowest elevation causing damage is 2-2.5 degrees C. Low elevations require longer durations and as the elevation increases, the time required is reduced logarithmically. Heat-induced defects are most common in the central nervous system (CNS) and include open neural tube, microencephaly, microphthalmia and neurogenic contractures. Apoptotic cells are found in these organs soon after threshold doses of heat. The periods of high susceptibility are brief, occurring at the time of organ induction and, paradoxically, at this stage, chaperone protein synthesis is at high levels, presumably to protect this process. Susceptibility might be due to gene activity being concentrated into organ induction with chaperone proteins being unavailable for repair of heat-denatured proteins. With activation of the HS response, normal protein synthesis is suspended (perhaps including those controlling induction of organs) and protective HS proteins are produced which rescue the embryo, but survival is achieved at the expense of normal development.
Edwards
M J
MJ
School of Anatomy, The University of New South Wales, NSW, 2052, Australia.
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002490:Central Nervous System / Q000002:abnormalities / Q000196:embryology; D000013:Congenital Abnormalities / Q000209:etiology; D005314:Embryonic and Fetal Development; D005260:Female; D005334:Fever / Q000503:physiopathology; D006358:Hot Temperature / Q000009:adverse effects*; D008297:Male; D009374:Neoplasms, Experimental / Q000209:etiology; D011247:Pregnancy