THE TRANSFORMING PROPERTIES OF THE MEIS1 GENE FAMILY

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DESCRIPTION: (Adapted from the investigator's abstract) BXH-2 mice develop a high incidence of myeloid leukemia that is causally associated with the expression of an ecotropic murine leukemia virus (MuLV). The MuLVs act as insertional mutagens to alter the expression of cellular protooncogenes or tumor suppressor genes that contribute to leukemia. Dr. Buchberg has identified a new common site of integration, Meis1 (Myeloid ecotropic viral integration site 1), in BXH-2 myeloid tumors. Sequence analysis of Meis 1 reveals it to be a novel homeobox gene: the homeodomain of Meis1 is related to the PBX homeodomain family. PBX1 was identified as a Hox cofactor, cooperatively interacting with a subset of Hox genes in specifying its DNA target. Recent evidence has demonstrated that Meis1 can interact with a number of other homeodomain containing proteins, including a subset of Hox proteins, as well as Pbx1. This interaction, in some instances, results in the increased stabilization of protein-DNA complexes and is required for the nuclear localization of PBX proteins. The specific aims of this proposal are designed to understand how Meis1 cooperates with its partners to contribute to transformation. Specifically, Dr. Buchberg will dissect the interaction between Meis1 and other homeodomain containing proteins by both in vitro and in vivo assays. These aims will ultimately identify the domains required for transformation in a bioassay and correlate physical interactions with biological interactions. Moreover, using the yeast-two hybrid assay and protein pull-down assays, additional proteins will be identified that interact with the various spliced forms of Meis1, to begin the functional dissection of the alternative forms of Meis1. The goals of this proposal are to understand the molecular basis of cellular transformation mediated by Meis1.