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HEAT SHOCK PROTEIN FUNCTION AS A THERAPEUTIC TARGET

热休克蛋白功能作为治疗靶点

基本信息

批准号：
6173380
负责人：
LUKE J WHITESELL
金额：
$ 10.72万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-05-01 至 2002-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6173380
关键词：
SCID mouse antibiotics breast neoplasms estrogen receptors gene induction /repression growth factor receptors human tissue intermolecular interaction neoplastic cell oncoproteins stress proteins transcription factor xenotransplantation

项目摘要

DESCRIPTION: The investigator's recent studies have implicated the selective interaction of geldanamycin (GA) with certain cellular heat shock proteins in mediating anti-tumor activity, but the specific molecular consequences of this interaction in clinically relevant tumor models remain unclear. In this application, studies are proposed which will examine GA effects on the assembly and function of two heat shock protein-containing multimolecular complexes known to be important in the biology of many breast cancers; namely, the estrogen receptor (ER) and mutant p53. Reconstitution experiments using reticulocyte lysate will be used to identify the specific components of the ER and p53 complexes and assess drug effects on the dynamics of complex assembly. At the whole-cell level, GA effects on steady state-expression, subcellular localization and transcriptional transactivating activity of the two targets will be examined. Lastly, p53 and ER expression will be examined in breast tumor xenografts growing in SCID mice treated with GA. These experiments should define useful biologic endpoints for drug action in vivo and will allow assessment of the significance of the molecular effects observed in tissue culture for tumorigenicity in animals.

描述：研究人员最近的研究表明，格尔德霉素（GA）与一定细胞热的选择性相互作用休克蛋白介导的抗肿瘤活性，但具体这种相互作用在临床相关肿瘤中的分子后果模型仍然不清楚。在本申请中，提出了研究，将检查GA对两个热休克的组装和功能的影响，已知含蛋白质的多分子复合物在许多乳腺癌的生物学;即，雌激素受体（ER）和突变型p53。使用网织红细胞裂解物的复溶实验将用于鉴定ER和p53复合物的特定组分并评估药物对复杂组装动力学的影响。在全细胞水平，GA对稳态表达的影响，亚细胞定位和转录反式激活活性的两个将对目标进行审查。最后，将检查p53和ER表达在用GA处理的SCID小鼠中生长的乳腺肿瘤异种移植物中。这些实验应确定药物作用的有用生物学终点，并将允许评估分子的意义，在动物致瘤性组织培养中观察到的影响。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Destabilization of steroid receptors by heat shock protein 90-binding drugs: a ligand-independent approach to hormonal therapy of breast cancer.

DOI：
发表时间：
2001-07
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
R. Bagatell;Omar Khan;G. Paine-Murrieta;C. Taylor;S. Akinaga;L. Whitesell
通讯作者：
R. Bagatell;Omar Khan;G. Paine-Murrieta;C. Taylor;S. Akinaga;L. Whitesell

Stable and specific binding of heat shock protein 90 by geldanamycin disrupts glucocorticoid receptor function in intact cells.

格尔德霉素与热休克蛋白 90 的稳定和特异性结合会破坏完整细胞中的糖皮质激素受体功能。

DOI：
10.1210/mend.10.6.8776730
发表时间：
1996
期刊：
Molecular endocrinology (Baltimore, Md.)
影响因子：
0
作者：
Whitesell,L;Cook,P
通讯作者：
Cook,P

Induction of a heat shock factor 1-dependent stress response alters the cytotoxic activity of hsp90-binding agents.

DOI：
发表时间：
2000-08
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
R. Bagatell;G. Paine-Murrieta;C. Taylor;Elizabeth J. Pulcini;S. Akinaga;I. Benjamin;L. Whitesell
通讯作者：
R. Bagatell;G. Paine-Murrieta;C. Taylor;Elizabeth J. Pulcini;S. Akinaga;I. Benjamin;L. Whitesell