Protective and adaptive responses of cells to injury are essential to survival and reproduction of all biological systems. Cancer cells are known to utilize adaptive mechanisms, often with adverse effects on therapeutic outcome, e.g., multidrug resistance. The cellular stress response is a major aspect of cellular adaptation to both disease and to therapy, and has been increasingly implicated in a wide spectrum of disease processes, including those leading to cancer. A highly conserved set of heat shock proteins (HSPs), part of the cellular stress response, therefore, have become the focus of many scientific studies in recent years. Our ongoing research has identified a major novel aspect of the cellular stress response that needs to be understood in the context of HSPs and cellular adaptation mechanisms. The focus of our project is the role of protein glycosylation in the cellular stress response. Cells that are stressed by hyperthermia, are known to increase the synthesis of major HSPs,while developing a transient state of heat resistance, known as thermotolerance. Concurrently, they show increased activity of certain glycosyltransferases and increased synthesis of specific glycoproteins, e.g., GP50. We hypothesize that both stress-induced glycoproteins and major HSPs are essential for cellular adaptation and the full expression of thermotolerance. Other stress conditions such as hypoxia, and treatments with peroxides, also activate a stress response that include elements of the heat shock response, and lead to the expression of tolerance.
Specific Aims are directed at the major heat-induced glycosylation product, i.e., the 50 Kd glycoprotein GP50. The proposed research will examine:
AIM 1) the structure of GP50, Aim 2) its function and its contribution to the expression of thermotolerance. Functional studies will utilize microinjection techniques, and a rare mutant in O-linked glycosylation.
Aim 3) Another major objective is the characterization of glycosylation and HSP synthesis induced by hypoxia and by hydrogen peroxide, as well as their functional consequences to cell survival under stress conditions. Understanding mechanisms of the general stress response offers potential applications in many areas of medicine. In oncology, adjunct use of hyperthermia with drugs and X-irradiation continues to be supported by a strong biological rationale, while stress responses induced by hypoxia/reoxygenation are relevant to not only to tumors, but also to injury following infarcts and transient hypoxia in various organ systems.
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