LIN-12/Notch proteins are receptors that mediate cell-cell interactions that specify cell fate during animal development. Notch activity plays a prominent role in many cell fate decisions in mammalian development. During adulthood, Notch activity continues to play important roles in renewing populations, including stem cells, the immune system, and epithelial cells. Aberrant, constitutive activation of LIN-12/Notch proteins causes certain cancers in human patients and in murine models;in other contexts, LIN-12/Notch activity can function as a tumor suppressor. Studies of LIN-12/Notch signaling in C. elegans have been, and continue to be, directly relevant to understanding the molecular mechanisms underlying normal mammalian development and serious human diseases. This proposal is concerned with identifying and characterizing genes that influence LIN-12/Notch signaling through powerful genetic methods in C. elegans. Genetic studies can identify and illuminate the roles of factors that influence LIN-12/Notch signaling and can inform new approaches to cancer treatment. For example, the same kinds of point mutations first described as activating C. elegans LIN-12/Notch were subsequently found to cause T acute lymphoblastic leukemia (T-ALL). Presenilin/gamma-secretase, first linked to LIN-12/Notch signaling through suppressors of activating point mutations in lin-12, is now a therapeutic target in clinical trials for combating T-ALL. Resistance to this therapy, however, has been linked to mutations in a tumor suppressor, SEL- 10/Fbw7, first isolated as a negative regulator of lin-12 activity in C. elegans. Like presenilin, new suppressors of activated LIN-12/Notch may identify new positive factors with the potential to serve as therapeutic targets;like SEL-10/Fbw7, new negative factors may illuminate processes that make tumors resistant to therapeutic agents. We propose four specific aims with these goals. First, to characterize new candidate positive regulators of lin-12/Notch activity obtained through an RNAi screen for suppressors of an activated LIN-12/Notch protein. Second, to identify molecularly a gene, sel-4, identified in a similar conventional genetic screen. Third, to identify new LIN-12 target genes, as past analysis indicates some LIN-12 target genes modulate lin-12 activity and cross-talk with other pathways. Fourth, to characterize new candidate negative regulators obtained in an RNAi screen and to explore a potential connection between RNAi and regulation of lin-12 activity.
LIN-12/Notch proteins are receptors that mediate cell-cell interactions that specify cell fate during animal development. Notch activity plays a prominent role in many cell fate decisions in mammalian development, and aberrant, constitutive activation of LIN- 12/Notch proteins causes certain cancers. This proposal is focused on identifying and characterizing genes that influence LIN-12/Notch signaling, exploiting the powerful genetic methods available in C. elegans.
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