THE TRANSFORMING PROPERTIES OF THE MEIS1 GENE FAMILY

描述：（改编自研究者摘要）BXH-2小鼠发育为 髓性白血病的高发病率与 嗜亲性鼠白血病病毒（MuLV）的表达。MuLV充当 插入诱变剂以改变细胞原癌基因的表达，或 导致白血病的肿瘤抑制基因布赫伯格博士发现 一个新的共同整合位点，Meis 1（髓样亲嗜性病毒整合 位点1），在BXH-2髓样肿瘤中。Meis 1的序列分析显示， Meis 1是一个新的同源异型盒基因：Meis 1的同源异型域与PBX相关 同源结构域家族PBX 1被鉴定为Hox辅因子， 与Hox基因的子集相互作用以指定其DNA靶标。最近 有证据表明，Meis 1可以与许多其他生物相互作用， 含有同源结构域的蛋白，包括Hox蛋白的子集，以及 Pbx1.在某些情况下，这种相互作用会导致 蛋白质-DNA复合物的稳定化，是核 PBX蛋白的定位。该提案的具体目标是 了解Meis 1如何与合作伙伴合作， 转型具体来说，布赫伯格博士将剖析 Meis 1和其他含有同源结构域的蛋白质，通过体外和体内研究 测定。这些目标将最终确定 生物测定中的转化，并将与 生物相互作用。此外，利用酵母双杂交试验和蛋白质 下拉测定，将鉴定与蛋白质相互作用的其他蛋白质。 Meis 1的各种剪接形式，以开始对 Meis 1的替代形式。本提案的目标是了解 Meis 1介导的细胞转化的分子基础。

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.