During normal growth, mammalian cells can encounter dramatic changes in their environment that adversely affect cellular processes and cause structural damage. To guard against this, cells have signaling pathways and checkpoints that allow them to detect these problems, activate protective responses if the damage is transient and can be resolved or self-destructive measures if the damage is not repairable. The pathways that monitor persistent damage have been the focus of intense research, and it is clear that components of these pathways are often the target of mutations in cancer cells, allowing them to escape destruction. When cells encounter adverse physiological conditions that interfere with protein folding, such as reduced levels of glucose or oxygen, they activate a protective pathway termed the unfolded protein response (UPR) that originates in the endoplasmic reticulum and serves to decrease protein translation, increase degradation, and induce cell cycle arrest. In addition to protecting tumor cells from unfavorable conditions, activation of the UPR alters the sensitivity of these cells to chemotherapeutic agents; making them resistant to topoisomerase II targeting drugs and more sensitive to DNA-crosslinking agents such as cisplatin. Because these drugs are very active in the treatment of childhood solid tumors, it is important to understand cellular pathways that contribute to drug sensitivity. The focus of this proposal is to determine how changes in drug sensitivity occur when the UPR is induced. Many of the protein components of the UPR have been identified, and genetic systems have been developed that specifically alter individual responses. These systems will be used to identify the UPR components that alter sensitivity to chemotherapeutic agents and to understand mechanistically how they cause reduced levels of topoisomerase II and increased sensitivity to crosslinking agents. Once the components and mechanisms have been determined, tumor cells will be engineered to interfere with these signaling components to directly assess the role they play in the in vivo growth of tumors and sensitivity to chemotherapeutic agents. The ability to modulate the protective responses of the UPR may ultimately provide us with a means to increase the efficacy of chemo- therapeutic intervention in combating childhood solid tumors.
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