REGULATION OF ONCOGENIC ACTIVITY BY DBL FAMILY PROTEINS

DBL 家族蛋白对致癌活性的调节

• 批准号: 6513358
• 负责人: IAN P WHITEHEAD
• 金额: $ 12.01万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6513358
• 关键词: biological signal transduction; catalyst; cell differentiation; cell line; epithelium; genetic regulation; human tissue; neoplastic transformation; oncogenes; protein binding; protein structure function; tissue /cell culture; transforming growth factors

DESCRIPTION: (dapted from applicant abstract) The Dbl-related oncogenes encode a large, structurally related family of growth regulatory proteins originally identified as transforming or invasion inducing(e.g., Dbs, Lfc and Lsc). Consequently , it is widely believed that the deregulated expression of Dbl family proteins can contribute to the aberrant growth, invasiveness and metastatic potential of tumor cells. Dbl proteins are activators of Rho family GTPases, and their transforming properties has been attributed to their aberrant upregulation of Rho activity. The large number of Dbl proteins that have been recently described, as well as the increasing number of their GPTase targets, is ample evidence of the important regulatory roles that these proteins will play in a multitude of biological processes. However, much remains to be learned about the mechanisms through which Dbl proteins mediate their biological activities, and about the contributions of these activities to human malignancies. Three specific aims are proposed to directly address these two important issues. First, although several studies have implicated the Rho proteins as the immediate targets of the Dbl protein transforming activity, there have been limited structure-based analyses done on the role of the catalytic activity in Dbl protein transformation. In specific Aim 1 the author will determine if Lfc transformation is dependent on its ability to bind, and activate RhoA. This approach will also generate valuable reagents that can be used to determine if Lfc is the critical link between extracellular signaling pathways and RhoA activation. Second, although the applicant has recently shown that Dbl proteins share a common ability to activate multiple signaling pathways (e.g., JNK, p38, SRF and NFKB), the contribution of any of these pathways to Dbl-mediated transformation, are unknown. In Specific Aim 2 he directly assess the contribution of JNK, p38 and NFKB to the transforming activity of the Dbs protein. Finally, transformation studies on Dbl protein have relied heavily on fibroblast cell systems. As a consequence the contribution of Dbl proteins to human carcinogenesis is still not known. In Specific Aim 3 the role of Lfc, Lsc and Dbs proteins in mediating the differentiation and invasive potential of the T47D human breast epithelial cell line will be examined. Based on his preliminary data, he anticipates that T47D will be an important system to address the contribution of the Dbl family proteins to epithelial cell transformation. Taken together, the investigator feels that these studies will contribute significantly to understand the mechanisms through which Dbl proteins contribute to aberrant cell growth and the development of human cancers.

描述：（摘自申请人摘要）Dbl相关癌基因 编码一个大的，结构相关的生长调节蛋白家族 最初被鉴定为转化或入侵诱导的（例如，德布斯，利物浦 LSC）。 因此，人们普遍认为， Db1家族蛋白的表达可导致异常生长， 肿瘤细胞的侵袭性和转移潜力。 Dbl蛋白是 Rho家族GTP酶的激活剂，及其转化特性已经被 这归因于它们的Rho活性的异常上调。 大量 的Dbl蛋白，最近已被描述，以及增加 他们的GPTase目标的数量，是重要的证据， 这些蛋白质将在许多生物学过程中发挥调节作用， 流程. 然而，关于这些机制， 哪些Dbl蛋白介导其生物活性，以及关于 这些活动对人类恶性肿瘤的贡献。 三个具体 提出了直接解决这两个重要问题的目标。 第一、 尽管有几项研究表明Rho蛋白是 Dbl蛋白转化活性的靶点， 对Dbl中催化活性的作用进行了基于结构的分析 蛋白质转化 在具体目标1中，作者将确定Lfc是否 转化依赖于其结合和激活RhoA的能力。 这 这种方法还将产生有价值的试剂，可用于确定 如果Lfc是细胞外信号通路之间的关键环节， RhoA激活。 第二，虽然申请人最近表明， 蛋白质具有激活多种信号通路的共同能力， (e.g., JNK，p38，SRF和NF κ B），这些途径中的任何一种对 Dbl介导的转化是未知的。 在《特定目标2》中，他直接 评估JNK，p38和NF κ B对转化活性的贡献。 DBS蛋白质 最后，Dbl蛋白的转化研究依赖于 严重影响成纤维细胞系统。 因此， Dbl蛋白对人类的致癌作用尚不清楚。 具体目标3 Lfc、Lsc和Dbs蛋白在介导分化中的作用， T47D人乳腺上皮细胞系的侵袭潜力将是 考察 根据他的初步数据，他预计T47D将是 一个重要的系统来解决Dbl家族蛋白质的贡献 到上皮细胞转化。 综合来看，调查人员认为 这些研究将大大有助于了解 Dbl蛋白促进异常细胞生长的机制， 人类癌症的发展。

项目成果

XGef mediates early CPEB phosphorylation during Xenopus oocyte meiotic maturation.

• DOI: 10.1091/mbc.e04-07-0585
• 发表时间: 2005-03
• 期刊: Molecular biology of the cell
• 影响因子: 3.3
• 作者: Susana E Martínez;Lei Yuan;C. Lacza;Heather Ransom;G. Mahon;I. Whitehead;L. Hake

Functional analysis of cdc42 residues required for Guanine nucleotide exchange.

鸟嘌呤核苷酸交换所需的 cdc42 残基的功能分析。

• DOI: 10.1074/jbc.m208580200
• 发表时间: 2002
• 期刊: The Journal of biological chemistry
• 作者: Rossman,KentL;Worthylake,DavidK;Snyder,JasonT;Cheng,Li;Whitehead,IanP;Sondek,John
• 通讯作者: Sondek,John

XGef is a CPEB-interacting protein involved in Xenopus oocyte maturation.

XGef 是一种参与非洲爪蟾卵母细胞成熟的 CPEB 相互作用蛋白。

• DOI: 10.1016/s0012-1606(02)00089-1
• 发表时间: 2003
• 期刊: Developmental biology
• 影响因子: 2.7
• 作者: Reverte,CarlosG;Yuan,Lei;Keady,BrianT;Lacza,Charlemagne;Attfield,KathleenR;Mahon,GwendolynM;Freeman,Benjamin;Whitehead,IanP;Hake,LauraE
• 通讯作者: Hake,LauraE