Tumor Necrosis Factor-alpha Signaling in Breast Cancer

乳腺癌中的肿瘤坏死因子-α 信号转导

基本信息

批准号：
7846326
负责人：
Alakananda Basu
金额：
$ 3.12万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2009-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7846326
关键词：
1-Phosphatidylinositol 3-Kinase 70-kDa Ribosomal Protein S6 Kinases Abbreviations Apoptosis Apoptotic Applications Grants Breast Cancer Cell CASP8 and FADD-like apoptosis regulating protein Caspase Cell Death Cell Proliferation Cell Survival Cells Cysteine Protease DDX6 gene Dominant-Negative Mutation Equilibrium Event Family Funding Genetic Growth Factor Isoenzymes Malignant Neoplasms Molecular Pathogenesis Pathway interactions Phosphorylation Phosphotransferases Play Protein Kinase C Protein-Serine-Threonine Kinases Proteins Proto-Oncogene Proteins c-akt Resistance Role Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Protein Staging Tumor Necrosis Factor-alpha Tumor Necrosis Factors caspase-9 citrate carrier cytokine kinase inhibitor malignant breast neoplasm neoplastic cell novel programs receptor suicidal tumor progression

项目摘要

DESCRIPTION (provided by applicant): Apoptosis is a highly orchestrated cell suicidal program required to maintain a balance between cell proliferation and cell death. Tumor necrosis factor-a (TNF), a pleotropic cytokine, plays an important role in immunesurveillance. The interaction of TNF with its receptors triggers activation of a family of cysteine proteases or caspases that are essential for the execution of cell death by apoptosis. The ability to evade cell death pathway is a critical event in cancer progression. Various pro- and antiapoptotic signal transduction pathways regulate activation of caspases by TNF. Protein kinase C (PKC), a family of serine/threonine kinases, plays a critical role in growth factor signal transduction pathway. During our previous funding period, we have shown that novel PKC isozymes act as anti-apoptotic proteins to inhibit cell death by TNF. The abundance of novel PKCs, however, was not sufficient to explain cellular sensitivity/resistance to TNF. A deregulation in Akt/protein kinase B (PKB) signal transduction pathway has been associated with the genesis of several cancers, including breast cancer although the molecular mechanism(s) by which this signaling pathway contributes to breast cancer pathogenesis is incompletely understood. We hypothesize that the PKC signal transduction pathway cooperates with components of the phosphatidylinositol 3-kinase (PI3K) pathway, such as PKB to regulate cell survival and cell death. The overall objective of this grant proposal is to delineate how a deregulation in PI3K/PKB signaling pathway that exists in breast cancer cells influences anti-apoptotic signaling by PKC. The long-term objective is to develop strategies to intervene with these pathways to inhibit progression of breast cancer.

描述（由申请人提供）：细胞凋亡是一种高度精心策划的细胞自杀程序，需要维持细胞增殖和细胞死亡之间的平衡。肿瘤坏死因子-a (TNF) 是一种多效性细胞因子，在免疫监视中发挥着重要作用。 TNF 与其受体的相互作用触发半胱氨酸蛋白酶或半胱天冬酶家族的激活，这对于通过细胞凋亡执行细胞死亡至关重要。逃避细胞死亡途径的能力是癌症进展中的关键事件。各种促凋亡和抗凋亡信号转导途径通过 TNF 调节半胱天冬酶的激活。蛋白激酶 C (PKC) 是丝氨酸/苏氨酸激酶家族，在生长因子信号转导途径中发挥着关键作用。在我们之前的资助期间，我们已经证明新型 PKC 同工酶可以作为抗凋亡蛋白来抑制 TNF 引起的细胞死亡。然而，大量的新型 PKC 不足以解释细胞对 TNF 的敏感性/耐药性。 Akt/蛋白激酶 B (PKB) 信号转导途径的失调与包括乳腺癌在内的多种癌症的发生有关，尽管该信号转导途径导致乳腺癌发病机制的分子机制尚不完全清楚。我们假设 PKC 信号转导途径与磷脂酰肌醇 3-激酶 (PI3K) 途径的成分（例如 PKB）协同调节细胞存活和细胞死亡。该拨款提案的总体目标是阐明乳腺癌细胞中存在的 PI3K/PKB 信号通路的失调如何影响 PKC 的抗凋亡信号传导。长期目标是制定干预这些途径的策略，以抑制乳腺癌的进展。

项目成果

期刊论文数量（28）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Deregulation of PKB influences antiapoptotic signaling by PKC in breast cancer cells.

PKB 的失调会影响乳腺癌细胞中 PKC 的抗凋亡信号传导。

DOI：
发表时间：
2004-09
期刊：
影响因子：
5.2
作者：
Lu, Dongmei;Huang, Jie;Basu, Alakananda
通讯作者：
Basu, Alakananda

Manipulation of PKC isozymes by RNA interference and inducible expression of PKC constructs.

通过 RNA 干扰和 PKC 构建体的诱导表达来操纵 PKC 同工酶。

DOI：
发表时间：
2008
期刊：
影响因子：
0
作者：
Basu, Alakananda;Persaud, Shalini D;Sivaprasad, Usha
通讯作者：
Sivaprasad, Usha

Protein kinase Cepsilon activates protein kinase B/Akt via DNA-PK to protect against tumor necrosis factor-alpha-induced cell death.

蛋白激酶 Cepsilon 通过 DNA-PK 激活蛋白激酶 B/Akt，以防止肿瘤坏死因子-α 诱导的细胞死亡。

DOI：
10.1016/j.jmb.2008.11.036
发表时间：
2009-01-23
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Yajima, Hrohiko;Lee, Kyung-Jong;Zhang, Shichuan;Kobayashi, Junya;Chen, Benjamin P. C.
通讯作者：
Chen, Benjamin P. C.

Overexpression of protein kinase C-eta attenuates caspase activation and tumor necrosis factor-alpha-induced cell death.

蛋白激酶 C-eta 的过度表达会减弱 caspase 激活和肿瘤坏死因子-α 诱导的细胞死亡。