THE TRANSFORMING PROPERTIES OF THE MEIS1 GENE FAMILY

描述：(改编自研究人员的摘要)BXH-2小鼠发育成 髓系白血病的高发病率与 生态型小鼠白血病病毒(MuLV)的表达MuLV扮演着 插入诱变剂以改变细胞原癌基因或 导致白血病的肿瘤抑制基因。布赫伯格博士已经确定 一种新的共同整合部位--MEIS1(髓系嗜生态病毒整合 位点1)，在BXH-2髓系肿瘤中。MEIS 1的序列分析揭示了它 一个新的同源框基因：Meis1的同源结构域与PBX相关 同源域家族。Pbx1被鉴定为HOX辅助因子 与HOX基因的一个子集相互作用，以确定其DNA靶标。近期 有证据表明，Meis1可以与许多其他 含有同源结构域的蛋白质，包括HOX蛋白质的子集，以及 Pbx1。在某些情况下，这种相互作用会导致 蛋白质-DNA复合体的稳定，这是核所必需的 PBX蛋白的定位。这项建议的具体目标是 了解Meis1如何与其合作伙伴合作，为 转型。具体地说，布赫伯格博士将剖析 Meis1等含有同源结构域的蛋白质的体内外研究 化验。这些目标最终将确定所需的域 生物测定中的变化及其与物理相互作用 生物相互作用。此外，还使用了酵母双杂交试验和蛋白质 下拉试验，将确定更多的蛋白质与 各种剪接形式的Meis1，开始功能解剖 MEIS1的替代形式。这项建议的目标是了解 Meis1介导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.