ROLE OF P270 IN DIFFERENTIATION AND TUMORIGENESIS

描述(申请人描述)：最近分离到的果蝇和 许多酵母SWI/SNF复合体成员的哺乳动物同源物表明 这些复合体在所有生物的细胞生长和发育过程中对基因表达的调控起着基础性的作用。其中一些蛋白质的改变与肿瘤的发生表型有关。人类SWI2同源物BRG1和hBrm已在癌细胞系C33和SW13中被证实丢失。在恶性横纹肌样瘤中发现了hSNF5/INI1基因的双等位基因改变。P270是人SWI/SNF复合体的一个重要成员，在我的实验室通过与p300和CBP共同的抗原性首次被鉴定。序列分析 P270的同源物表明它是哺乳动物中的SWI1同源物。P270在SWI/SNF复合体中的功能尚不清楚，但某些基序提供了线索。P270含有四个LxxLL基序，可与核激素受体结合。P270还包含一个最近定义的ARID(AT-Rich相互作用域)DNA结合共识序列。P270的这些区域及其在SWI/SNF复合体中的位置，似乎介导了组织特异性基因的表达和 为了包含染色质重塑活动，提出了p270作为激素信号和转录启动的整合因子的潜在功能。P270的这一潜在功能表明，它将在激素驱动的分化中发挥重要作用。我建议研究p270的结构和功能关系，重点是LxxL1基序的作用和该蛋白在核上的活性 分化过程中的激素信号，重点是糖皮质激素驱动的脂肪细胞分化。具体地说，我建议：确定p270中LxxL1基序介导的蛋白质相互作用；确定激素对p270活性和表达的影响；以及确定 P270参与细胞生长调控。

DESCRIPTION (Applicant's Description): Recent isolation of Drosophila and mammalian homologs of many of the yeast SWI/SNF complex members suggest that these complexes play fundamental roles in the regulation of gene expression during cell growth and development in all organisms. Alterations in some of these proteins have been associated with the tumorigenic phenotype. Loss of the human SWI2 homologs Brg1 and hBrm have been demonstrated in the cancer cell lines C33 and SW13. Biallelic alterations of the hSNF5/INI1 gene were discovered in malignant rhabdoid tumors. p270 is an integral member of human SWI/SNF complexes, first identified in my lab through its shared antigenic specificity with p300 and CBP. Sequence analysis of p270 suggests it is the mammalian homolog of SWI1. The function of p270 in the SWI/SNF complex is not known, but certain motifs provide a clue. p270 contains four LXXLL motifs demonstrated to bind nuclear hormone receptors. p270 also contains a recently defined ARID (AT-Rich Interaction Domain) DNA binding consensus sequence. These regions of p270 and its location in the SWI/SNF complex, which appears to mediate tissue specific gene expression and to contain chromatin remodeling activities, suggest a potential function for p270 as an integrator of hormone signaling and transcription initiation. This potential function of p270 suggests it will play an important role in hormonally driven differentiation. I propose to study the structure and function relationship of p270 with a focus on the roles of the LXXLL motifs and activity of the protein on nuclear hormone signaling during differentiation, with an emphasis on glucocorticoid driven adipocyte differentiation. Specifically I propose to: identify the protein interactions mediated by the LXXLL motifs in p270; determine the effect of hormones on activity and expression of p270; and determine whether p270 contributes to cell growth control.