STRESS ACTIVATED PROTEIN KINASES AND CHEMOTHERAPY
STRESS ACTIVATED PROTEIN KINASES AND CHEMOTHERAPY
批准号:
2871974
负责人:
TIMOTHY C. CHAMBERS
金额:
$16.22万
依托单位国家:
美国
项目类别:
财政年份:
1998
资助国家:
美国
项目状态:
已结题
起止时间:
1998-04-01 至 2002-01-31
关键词:
AP1 protein antineoplastics antisense nucleic acid apoptosis biological signal transduction cysteine endopeptidases cytotoxicity doxorubicin enzyme activity enzyme inhibitors etoposide gene expression immunocytochemistry multidrug resistance neoplasm /cancer chemotherapy oligonucleotides oncoproteins pharmacokinetics phosphorylation protein kinase protooncogene tissue /cell culture transcription factor vinblastine western blottings
中文摘要
大多数抗癌药物的主要作用机制是已知的,
许多诱导凋亡。 然而,我们的知识存在很大的差距,
抗癌药物的作用,特别是如何损害和细胞凋亡,
分子连接。 此外,细胞死亡并不总是随之而来,
损伤,癌细胞可以通过暴露于细胞毒性药物而存活,
有缺陷的细胞凋亡、其他抗性机制或修复。 一个
对损伤与反应之间联系机制的理解可能表明,
改变细胞死亡阈值的方法,
对化疗药物敏感。 最近,我们已经证明,
阿霉素、长春碱或依托泊苷激活c-Jun NH 2-末端
蛋白激酶(JNK),一种人KB中的应激活化蛋白激酶
癌细胞 我们的假设是JNK介导的信号传导是一种
应激反应的关键组成部分,
可能通过影响或介导影响结局的抗癌药物
细胞死亡或细胞存活。 在具体目标1中,底物
(转录因子)和效应子(转录激活因子)
将确定响应于化疗药物的JNK。 这将
提供下游分子事件的全面情况
可能对化疗的总体反应至关重要。
在具体目标2中,几种方法(JNK反义寡核苷酸,
JNK磷酸酶过表达,SEK 1的显性负性抑制剂,
Jun或ATF-2)将用于产生人癌细胞系,
JNK信号传导缺陷的患者。 在
具体目标3,JNK信号传导缺陷细胞系将用于
探讨JNK激活与
对化疗药物的应答的凋亡性细胞死亡。 在
具体地,将确定JNK是否调节表达
或凋亡调节因子(Bcl-2家族)的活性或凋亡效应
(半胱天冬酶)。 在具体目标4中,将确定JNK是否发挥作用
通过调节MDR 1表达在细胞存活中的作用。 通过
了解JNK在癌细胞对
抗癌药物,我们也许能够开发出操纵这种方法的方法。
信号通路,以增加药物敏感性或防止药物
阻力
英文摘要
The primary mechanism of action of most anticancer dugs are known and
many induce apoptosis. However, there are large gaps in our knowledge
of anticancer drug action, in particular how damage and apoptosis are
molecularly linked. Furthermore, cell death does not always follow
damage, and cancer cells can survive exposure to cytotoxic drugs through
defective apoptosis, other resistance mechanisms, or repair. An
understanding of the mechanisms that link damage to response may suggest
ways to alter the threshold for cell death to make cancer cells more
sensitive to chemotherapeutic drugs. Recently, we have shown that
Adriamycin, vinblastine, or etoposide activate c-Jun NH2-terminal
protein kinase (JNK), a stress-activated protein kinase, in human KB
carcinoma cells. Our hypothesis is that JNK-mediated signaling is a
critical component of the stress response to functionally distinct
anticancer drugs that might affect outcome by influencing or mediating
cell death or cell survival. In Specific Aim 1, the substrates
(transcription factors) and effectors (transcriptional activators) of
JNK in response to chemotherapeutic drugs will be determined. This will
provide a comprehensive picture of molecular events emanating downstream
from JNK that may be critical to the overall response to chemotherapy.
In Specific Aim 2, several approaches (JNK antisense oligonucleotides,
JNK phosphatase overexpression, dominant negative inhibitors of SEK1,
Jun or ATF-2) will be used to generate human carcinoma cell lines with
defective JNK signaling in response to chemotherapeutic drugs. In
Specific Aim 3, the JNK signaling-defective cell lines will be used to
explore the mechanistic relationship between JNK activation and
apoptotic cell death in response to chemotherapeutic drugs. In
particular, it will be determined whether JNK regulates the expression
or activity of apoptotic regulators (Bcl-2 family) or apoptotic effects
(caspases). In Specific Aim 4, it will be determined whether JNK plays
a role in cell survival through regulation of MDR1 expression. By
understanding the role of JNK in the response of carcinoma cells to
anticancer drugs, we may be able to develop methods to manipulate this
signaling pathway in order to increase drug sensitivity or prevent drug
resistance.
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会议论文
BcL-2 Proteins in Mechanism of Anti-mitotic Drug Action
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批准号:7232016
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项目类别:
-
资助金额:$22.08万
-
财政年份:2004
-
负责人:TIMOTHY C. CHAMBERS
-
依托单位:
BcL-2 Proteins in Mechanism of Anti-mitotic Drug Action
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批准号:6825903
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项目类别:
-
资助金额:$25.34万
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财政年份:2004
-
负责人:TIMOTHY C. CHAMBERS
-
依托单位:
BcL-2 Proteins in Mechanism of Anti-mitotic Drug Action
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批准号:7105497
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项目类别:
-
资助金额:$22.74万
-
财政年份:2004
-
负责人:TIMOTHY C. CHAMBERS
-
依托单位:
Bcl-2 Proteins in Mechanism of Anti-mitotic Drug Action
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批准号:8097482
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项目类别:
-
资助金额:$22.72万
-
财政年份:2004
-
负责人:TIMOTHY C. CHAMBERS
-
依托单位:
Bcl-2 Proteins in Mechanism of Anti-mitotic Drug Action
-
批准号:8468921
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项目类别:
-
资助金额:$21.36万
-
财政年份:2004
-
负责人:TIMOTHY C. CHAMBERS
-
依托单位:
BcL-2 Proteins in Mechanism of Anti-mitotic Drug Action
-
批准号:7423961
-
项目类别:
-
资助金额:$22.08万
-
财政年份:2004
-
负责人:TIMOTHY C. CHAMBERS
-
依托单位:
BcL-2 Proteins in Mechanism of Anti-mitotic Drug Action
-
批准号:6911501
-
项目类别:
-
资助金额:$23.29万
-
财政年份:2004
-
负责人:TIMOTHY C. CHAMBERS
-
依托单位:
Bcl-2 Proteins in Mechanism of Anti-mitotic Drug Action
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批准号:7985884
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项目类别:
-
资助金额:$23.42万
-
财政年份:2004
-
负责人:TIMOTHY C. CHAMBERS
-
依托单位:
Bcl-2 Proteins in Mechanism of Anti-mitotic Drug Action
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批准号:8677736
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项目类别:
-
资助金额:$22.04万
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财政年份:2004
-
负责人:TIMOTHY C. CHAMBERS
-
依托单位:
Bcl-2 Proteins in Mechanism of Anti-mitotic Drug Action
-
批准号:8267701
-
项目类别:
-
资助金额:$22.72万
-
财政年份:2004
-
负责人:TIMOTHY C. CHAMBERS
-
依托单位:
Prostate tumor progression by mitochondrial DNA change
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批准号:8461704
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项目类别:
-
资助金额:$21.88万
-
财政年份:2003
-
负责人:TIMOTHY C. CHAMBERS
-
依托单位:
STRESS ACTIVATED PROTEIN KINASES AND CHEMOTHERAPY
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批准号:2606596
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项目类别:
-
资助金额:$16.83万
-
财政年份:1998
-
负责人:TIMOTHY C. CHAMBERS
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依托单位:
Stress-activated Protein Kinases and Chemotherapy
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批准号:6943028
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项目类别:
-
资助金额:$21.3万
-
财政年份:1998
-
负责人:TIMOTHY C. CHAMBERS
-
依托单位:
Stress-activated Protein Kinases and Chemotherapy
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批准号:6652104
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项目类别:
-
资助金额:$21.3万
-
财政年份:1998
-
负责人:TIMOTHY C. CHAMBERS
-
依托单位:
Stress-activated Protein Kinases and Chemotherapy
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批准号:6799018
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项目类别:
-
资助金额:$4.14万
-
财政年份:1998
-
负责人:TIMOTHY C. CHAMBERS
-
依托单位:
Stress-activated Protein Kinases and Chemotherapy
-
批准号:6764631
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项目类别:
-
资助金额:$2.06万
-
财政年份:1998
-
负责人:TIMOTHY C. CHAMBERS
-
依托单位:
STRESS ACTIVATED PROTEIN KINASES AND CHEMOTHERAPY
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批准号:6150260
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项目类别:
-
资助金额:$16.71万
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财政年份:1998
-
负责人:TIMOTHY C. CHAMBERS
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依托单位:
STRESS ACTIVATED PROTEIN KINASES AND CHEMOTHERAPY
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批准号:6350246
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项目类别:
-
资助金额:$17.21万
-
财政年份:1998
-
负责人:TIMOTHY C. CHAMBERS
-
依托单位:
Stress-activated Protein Kinases and Chemotherapy
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批准号:6541824
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项目类别:
-
资助金额:$20.25万
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财政年份:1998
-
负责人:TIMOTHY C. CHAMBERS
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依托单位:
Stress-activated Protein Kinases and Chemotherapy
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批准号:6801128
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项目类别:
-
资助金额:$21.3万
-
财政年份:1998
-
负责人:TIMOTHY C. CHAMBERS
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依托单位:
海外基金