MOLECULAR MECHANISMS OF NOTCH SIGNALING IN NEOPLASIA

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DESCRIPTION: (Adapted from applicant's abstract) Notch genes play a central role in both development and disease. Notch proteins are large transmembrane receptors with no apparent enzymatic activity. Although ligands (Serrate) for Notch have been identified, the mechanism of ligand activation and downstream signaling remains poorly understood. Mutations in the Notch signal transduction family are implicated in a number of human disorders. In T-cell Acute Lymphoblastic Leukemia (T-ALL), the Notch 1 locus is involved in a chromosomal translocation with the T-cell recpetor B locus {t(7:9)(q34;q34.3)}. This translocation generates aberrant Notch proteins that lack most of the extracellular sequences. These mutant forms of Notch are thought to be constitutively active; however, the pathophysiological mechanism is unknown. In addition to the involvement of Notch in T-cell leukemia, expression studies have revealed aberrant expression of both Notch and Serrate proteins in other neoplasm including cervical and colorectal carcinoma. The long term goal of this laboratory is to elucidate the mechanisms of Notch signaling in neoplasia. The research proposed in this application is focused on the dissection of the Notch signaling pathway using molecular genetics and biochemistry. Their laboratory has developed an in vitro transformation model for Notch proteins. Activated mutants of Notch that resemble those found in T-ALL are capable of transforming cells in collaboration with E1A. Using this assay, a structure/function analysis will be performed to determine the domains of Notch required for transformation. Other aspects of this work will be directed toward identifying proteins that interact with Notch and determination of the role these proteins play in Notch-mediated transformation. Cellular transformation is a culmination of a number of defects in certain cellular processes, such as apoptosis and cell cycle control. To investigate the role of Notch in such processes a conditionally transforming allele of Notch will be created. A conditional allele of Notch will be useful in studying the early events in neoplastic conversion. Moreover, a conditional allele of Notch will allow us to address the requirement of Notch signaling events in the initiation and maintenance of transformation. The role that Serrate (Notch ligand) plays in activation of Notch and neoplastic transformation will also be studied.