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：
7577642
负责人：
Alakananda Basu
金额：
$ 4.4万
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：
1997
资助国家：
美国
起止时间：
1997-09-04 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7577642
关键词：
1-Phosphatidylinositol 3-Kinase 70-kDa Ribosomal Protein S6 Kinases Abbreviations Apoptosis Apoptotic Applications Grants BAD gene Bad protein 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 LY294002 Malignant Neoplasms Molecular Pathogenesis Pathway interactions Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide Phosphorylation Phosphotransferases Play Protein Kinase C 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 human TNF protein kinase inhibitor malignant breast neoplasm neoplastic cell novel programs receptor suicidal tumor progression

项目摘要

Apoptosis is a highly orchestrated cell suicidal program required to maintain a balance between cell proliferation and cell death. Tumor necrosis factor-o_ (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 serinelthreonine 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 PKCo The long- term objective is to develop strategies to intervene with these pathways to inhibit progression of breast cancer.

细胞凋亡是一种高度精心策划的细胞自杀程序，需要维持细胞之间的平衡增殖和细胞死亡。肿瘤坏死因子-o_ (TNF) 是一种多效性细胞因子，在在免疫监视中发挥重要作用。 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，对于执行细胞死亡至关重要细胞凋亡。逃避细胞死亡途径的能力是癌症进展中的关键事件。各种各样的促凋亡和抗凋亡信号转导途径通过 TNF 调节 Caspases 的激活。蛋白质激酶 C (PKC) 是丝氨酸和苏氨酸激酶家族，在生长因子信号中发挥着关键作用转导途径。在我们之前的资助期间，我们已经展示了新颖的 PKC 同工酶充当抗凋亡蛋白，抑制 TNF 导致的细胞死亡。丰富的新型 PKC，然而，这不足以解释细胞对 TNF 的敏感性/耐药性。放松管制 Akt/蛋白激酶 B (PKB) 信号转导途径与以下疾病的发生有关多种癌症，包括乳腺癌，尽管这种情况的分子机制信号通路对乳腺癌发病机制的影响尚不完全清楚。我们假设 PKC 信号转导通路与磷脂酰肌醇3激酶（PI3K）途径，例如PKB来调节细胞存活和细胞死亡。本拨款提案的总体目标是描述如何放松 PI3K/PKB 信号传导的管制乳腺癌细胞中存在的通路影响 PKCo 的抗凋亡信号传导长期目标是制定干预这些途径的策略，以抑制疾病的进展乳腺癌。