CAF, A COACTIVATOR OF FOS, AND BREAST CANCER

CAF、FOS 的协同激活剂和乳腺癌

• 批准号: 6124492
• 负责人: EDWARD B LEOF
• 金额: $ 20.45万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-17 至 2001-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6124492
• 关键词: beta galactosidase; binding proteins; breast neoplasms; carcinogenesis; fibroblasts; fos protein; gene mutation; genetic promoter element; genetic regulation; human tissue; immunocytochemistry; molecular oncology; myoblasts; neoplasm /cancer genetics; neoplastic process; nucleic acid sequence; posttranslational modifications; transcription factor; transforming growth factors; virus protein

Recent studies in our laboratory have established that progression to invasive human breast cancer is accompanied by the activation of tissue factor (TF)-expressing myofibroblasts, a stromal response to carcinoma cell-derived members of the TGF-beta family of growth factors. Futhermore, TGF-beta1-dependent activation of TF gene transcription in myofibroblast-like cells in vitro requires c-Fos-containing AP-1 DNA- binding heterodimers and TF basal promoter-specific factor with functional properties characteristic of a transcriptional coactivator. This putative coactivator of Fos (CAF) appears distinct from CBP/p300 family of coactivators, but like CBP/p300, functionally interacts with both c-Fos and the adenovirus E1A12s protein. Importantly, the ability of CAF to mediate functional interactions with c-Fos is dependent upon TGF-beta1 signaling. In this research, we will 1) map E1A domains which specifically interact with CAF, 2) utilize this information to partially characterize CAF and to isolate CAF protein and cDNA for sequence analysis, 3) determine how the functional activity of CAF is modulated by TGF-beta1 signaling, and 4) probe for the expression of CAF in breast cancer myofibroblasts in vivo. These studies should illuminate a novel downstream target of TGF-beta signaling in myofibroblasts and may ultimately establish CAF as an essential mediator of carcinoma cell- stromal interactions which contribute to breast cancer progression.

我们实验室的最新研究确定了发展 侵入性人类乳腺癌伴随着组织的激活 因子（TF）表达肌纤维细胞，对癌的基质反应 TGF-beta生长因子家族的细胞衍生成员。 festhermore，tgf-beta1依赖于TF基因转录的激活 体外成肌纤维细胞样细胞需要含有C的AP-1 DNA- 结合异二聚体和TF基础启动子特异性因子与 转录共激活因子的功能特性。 该推定的FOS（CAF）共同激活因子似乎与CBP/P300不同 共激活因子家族，但像CBP/P300一样，在功能上与 C-FOS和腺病毒E1A12S蛋白。 重要的是，能力 CAF介导与C-FOS的功能相互作用的取决于 TGF-BETA1信号传导。 在这项研究中，我们将1）映射E1A域 特别与CAF互动，2）利用此信息部分 表征CAF和分离CAF蛋白和cDNA的序列 分析，3）确定如何调制CAF的功能活动 通过TGF-BETA1信号传导，4）探针在乳房中表达CAF 癌症肌纤维细胞在体内。 这些研究应该照亮小说 肌纤维细胞中TGF-beta信号的下游目标，可能 最终将CAF建立为癌细胞癌的必要介质 有助于乳腺癌进展的基质相互作用。

项目成果

Suppression of tissue factor expression, cofactor activity, and metastatic potential of murine melanoma cells by the N-terminal domain of adenovirus E1A 12S protein.

腺病毒 E1A 12S 蛋白 N 末端结构域抑制小鼠黑色素瘤细胞的组织因子表达、辅因子活性和转移潜力。

• DOI: 10.1002/jcb.10099
• 发表时间: 2002
• 期刊: Journal of cellular biochemistry
• 影响因子: 4
• 作者: Voigtländer,Constanze;Rand,Arlymae;Liu,Su-Ling;Wilson,TimothyJ;Pittelkow,MarkR;Getz,MichaelJ;KelmJr,RobertJ
• 通讯作者: KelmJr,RobertJ