ERBB RECEPTOR CONTROL OF BREAST CANCER GROWTH
ERBB 受体控制乳腺癌生长
基本信息
- 批准号:2896238
- 负责人:
- 金额:$ 22.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1998
- 资助国家:美国
- 起止时间:1998-09-30 至 2001-09-29
- 项目状态:已结题
- 来源:
- 关键词:active sites biological signal transduction breast neoplasms cell growth regulation cell line enzyme inhibitors epidermal growth factor growth factor receptors molecular cloning neoplastic cell protein kinase C receptor binding receptor expression site directed mutagenesis transfection yeast two hybrid system
项目摘要
A crucial role for Epidermal Growth Factor Receptor (erbB) family
members in development of breast cancer has been demonstrated over the
past 15 years. We have recently cloned a novel protein, EBP1, which
interacts with the cytoplasmic domain of erbB3. Treatment of cells with
the erbB-3 ligand, heregulin (HRG) induces the translocation of EBP1
from the cytoplasm to the nucleus. Overexpression of EBP1 inhibits
proliferation of human breast cancer cells. We propose to study the
physiological function of erbB-3EBP1 interactions in human breast cancer
cells. Understanding the regulation and consequences of these
interactions could lead to a better understanding of erbB-3 signal
transduction and to the definition of new therapeutic targets in breast
cancer.
First, to define the function of erbB-3-EBP1 interactions, we will a)
determine HRG-mediated interactions of EBP1 with other erbB receptors
and the dependence of such interactions on the expression of erbB-3
heterodimeric binding partners using the yeast-two hybrid system and
engineered murine cells expressing defined combinations of erbB
receptors 2) establish the colocalization of EBP1 and erbB-3 by confocal
microscopy before and after HRG treatment, c) determine the region of
EBP1 required for erbB-3 binding and the effects of expression of
different regions of EBP1 on HRG-mediated signalling using a series of
deletion and single site mutants of EBP1, d) determine the effects of
EBP1 overexpression on basal and HRG-induced cell growth and
differentiation using stable transfectants with inducible expression.
Second, we will determine the role of Protein Kinase C (PKC) in
modulating EBP1 activity. The sites of phosphorylation after HRG
treatment will be determined using tryptic phosphopeptide mapping and
phosphamino acid analysis. Effects of PKC inhibitors on EBP1 function
will be assessed in intact cells. Potential PKC sites will be mutated
and effects of such mutations on EBP1 function defined. Third, we will
define the significance of EBP1 nuclear localization. We will a)
determine if EBP1 is part of a multiprotein nuclear localization complex
by isolating EBP1 interacting proteins using the yeast two-hybrid system
b) define the role of EBP1 and its accessory transcriptional activators
using GAL4 DNA binding domain fusions c) identify preferred DNA binding
sites for EBP1 using a degenerate oligonucleotide strategy.
表皮生长因子受体(erbB)家族的重要作用
项目成果
期刊论文数量(0)
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ANNE W. HAMBURGER其他文献
ANNE W. HAMBURGER的其他文献
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{{ truncateString('ANNE W. HAMBURGER', 18)}}的其他基金
A Novel Mechanism for Control of Androgen Receptor Levels in HRPC
HRPC 中雄激素受体水平控制的新机制
- 批准号:
8260550 - 财政年份:2011
- 资助金额:
$ 22.74万 - 项目类别:
A Novel Mechanism for Control of Androgen Receptor Levels in HRPC
HRPC 中雄激素受体水平控制的新机制
- 批准号:
8038769 - 财政年份:2011
- 资助金额:
$ 22.74万 - 项目类别:
A Novel Mechanism for Control of Androgen Receptor Levels in HRPC
HRPC 中雄激素受体水平控制的新机制
- 批准号:
8447576 - 财政年份:2011
- 资助金额:
$ 22.74万 - 项目类别:
A novel therapy for HER2 positive hormone refractory breast cancer
HER2阳性激素难治性乳腺癌的新疗法
- 批准号:
7943990 - 财政年份:2009
- 资助金额:
$ 22.74万 - 项目类别:
A novel therapy for HER2 positive hormone refractory breast cancer
HER2阳性激素难治性乳腺癌的新疗法
- 批准号:
7814609 - 财政年份:2009
- 资助金额:
$ 22.74万 - 项目类别:
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