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：
7194279
负责人：
Alakananda Basu
金额：
$ 22.38万
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 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7194279
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 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 human TNF protein 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）：凋亡是一个高度精心策划的细胞自杀程序，以维持细胞增殖和细胞死亡之间的平衡。肿瘤坏死因子A（TNF）是一种多性细胞因子，在免疫监视中起重要作用。 TNF与其受体的相互作用触发了半胱氨酸蛋白酶或胱天蛋白酶家族的激活，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的关键事件。 TNF调节胱天蛋白酶激活的各种促凋亡信号转导途径。丝氨酸/苏氨酸激酶家族蛋白激酶C（PKC）在生长因子信号转导途径中起关键作用。在以前的资金期间，我们已经表明，新型的PKC同工酶充当抗凋亡蛋白可抑制TNF细胞死亡。然而，新型PKC的丰度不足以解释细胞对TNF的敏感性/抗性。在AKT/蛋白激酶B（PKB）信号转导途径中的放松管制与几种癌症的发生有关，包括乳腺癌，尽管该信号通路有助于乳腺癌发病机理的分子机制尚不完全理解。我们假设PKC信号转导途径与磷脂酰肌醇3-激酶（PI3K）途径（例如PKB）合作，例如调节细胞存活和细胞死亡。该赠款提案的总体目的是描述乳腺癌细胞中存在的PI3K/PKB信号通路中的放松管制如何影响PKC的抗凋亡信号传导。长期目标是制定策略来干预这些途径以抑制乳腺癌的进展。