The role of PIKE-S in mediating EGFR mitogenic signaling in OSCC cells

PIKE-S 在介导 OSCC 细胞中 EGFR 有丝分裂信号传导中的作用

基本信息

批准号：
7473291
负责人：
Zhongjian Xie
金额：
$ 7.79万
依托单位：
NORTHERN CALIFORNIA INSTITUTE/RES/EDU
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7473291
关键词：
1-Phosphatidylinositol 3-Kinase Affect Binding Carcinoma Cell Line Cell Nucleus Cells DNA biosynthesis DNA chemical synthesis Data Development Enhancers Epidermal Growth Factor Epidermal Growth Factor Receptor Goals Growth Growth Factor Guanine Nucleotide Exchange Factors Guanosine Triphosphate Ligands Malignant Epithelial Cell Mediating Molecular Target Neurons Nuclear Pathogenesis Pathway interactions Phospholipase C Phosphorylation Pike fish Primary Neoplasm Protein Kinase Protein Kinase C Protein Overexpression RNA-Binding Proteins Role SH3 Domains Signal Pathway Signal Transduction Site Stimulation of Cell Proliferation Theoretical model Transforming Growth Factors insight knock-down mouth squamous cell carcinoma neoplastic cell novel novel therapeutics nucleolin phosphatidylinositol 3,4,5-triphosphate prognostic response therapeutic target tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): One of the key drivers for the mitogenesis of oral squamous cell carcinoma (OSCC) cells is activation of the epidermal growth factor receptor (EGFR) by ligands such as epidermal growth factor (EGF) and transforming growth factor-a (TGF-a). However, the mechanism by which activated EGFR mediates OSCC cell mitogenesis is still unclear. Recent studies indicate that in neuronal cells never growth factor (NGF) stimulates phospholipase C-?1 (PLC-?1) translocation to the nucleus. The nuclear PLC-?1 acts as a guanine nucleotide exchange factor and activates the short form of phosphatidylinositol 3-OH kinase enhancer (PIKE-S) in the nucleus through its SH3 domain. The activated PIKE-S then stimulates nuclear phosphatidylinositol 3-OH kinase (PI3K) activity essential for cell mitogenesis. Our preliminary results show that PIKE-S is present in an OSCC cell line (SCC4 cells). EGF induces PLC-?1 translocation to the nucleus where it binds to the nuclear PIKE-S. PLC-?1 and PIKE-S are required for EGF-induced SCC4 cell mitogenesis. These data suggest a novel pathway for EGFR ligand-induced SCC4 cell mitogenesis. Our HYPOTHESIS is that nuclear PIKE-S activated by the SH3 domain of PLC-?1 is required for EGFR ligand-induced OSCC cell mitogenesis. EGFR ligand (EGF or TGF-a) stimulates nuclear PIKE-S through the SH3 domain of nuclear PLC-?1 and enhances nuclear PI3K activity. Phosphatidylinositol 3,4,5-triphosphate (PIP3) produced in the nucleus by PI3K attracts protein kinase C-? (PKC-?) to the nucleus to phosphorylate nucleolin, an RNA binding protein required for DNA synthesis. SPECIFIC AIMS: (1) Determine the cellular localization of PLC-?1, PIKE-S, PI3Ks and PKC-? in OSCC cells in response to EGF and TGF-a. (2) Determine whether PIKE-S interacts with PLC-?1 and PI3Ks, and whether knocking down PLC-?1 or overexpression of PLC-?1 in OSCC cells affects EGF- and TGF-a-induced nuclear PIKE-S, PI3Ks and PKC-? activation, nuclear nucleolin phosphorylation, OSCC cell mitogenesis, survival and invasion. (3) Determine the role of PIKE-S in mediating EGF- and TGF-a-induced nuclear PI3Ks and PKC-? activation, nuclear nucleolin phosphorylation, OSCC cell mitogenesis, survival and invasion. SIGNIFICANCE: These studies will uncover a novel pathway for EGF ligand induced OSCC mitogenesis and may provide therapeutic targets for OSCC. Narrative: Oral squamous cell carcinoma is the sixth most common type of carcinoma worldwide and the mechanism of uncontrolled tumor growth is unclear. These studies will provide insight into the mechanism important for epidermal growth factor induced oral squamous cell carcinoma growth. Understanding these mechanisms will bring the possibility of new molecular targets for development novel therapeutic options for the control of oral squamous cell carcinoma.

描述（由申请人提供）：口腔鳞状细胞癌（OSCC）细胞有丝分裂的关键驱动因素之一是通过表皮生长因子（EGF）和转化生长因子等配体激活表皮生长因子受体（EGFR）。 (TGF-a)。然而，激活的EGFR介导OSCC细胞有丝分裂的机制仍不清楚。最近的研究表明，在神经元细胞中，生长因子 (NGF) 不会刺激磷脂酶 C-α1 (PLC-α1) 易位至细胞核。核 PLC-α1 充当鸟嘌呤核苷酸交换因子，并通过其 SH3 结构域激活细胞核中短形式的磷脂酰肌醇 3-OH 激酶增强子 (PIKE-S)。激活的 PIKE-S 随后会刺激细胞有丝分裂所必需的核磷脂酰肌醇 3-OH 激酶 (PI3K) 活性。我们的初步结果表明 PIKE-S 存在于 OSCC 细胞系（SCC4 细胞）中。 EGF 诱导 PLC-α1 易位至细胞核，并与细胞核 PIKE-S 结合。 PLC-α1 和 PIKE-S 是 EGF 诱导的 SCC4 细胞有丝分裂所必需的。这些数据表明 EGFR 配体诱导 SCC4 细胞有丝分裂的新途径。我们的假设是，由 PLC-α1 的 SH3 结构域激活的核 PIKE-S 是 EGFR 配体诱导的 OSCC 细胞有丝分裂所必需的。 EGFR配体（EGF或TGF-a）通过核PLC-α1的SH3结构域刺激核PIKE-S并增强核PI3K活性。 PI3K 在细胞核中产生的磷脂酰肌醇 3,4,5-三磷酸 (PIP3) 吸引蛋白激酶 C-α (PKC-?) 进入细胞核，磷酸化核仁素，这是 DNA 合成所需的 RNA 结合蛋白。具体目标： (1) 确定 PLC-?1、PIKE-S、PI3Ks 和 PKC-? 的细胞定位OSCC 细胞对 EGF 和 TGF-a 的反应。 (2)确定PIKE-S是否与PLC-α1和PI3K相互作用，以及在OSCC细胞中敲除PLC-α1或PLC-α1的过度表达是否影响EGF和TGF-α诱导的核PIKE-S、PI3K和 PKC-？激活、核核素磷酸化、OSCC 细胞有丝分裂、存活和侵袭。 (3)确定PIKE-S在介导EGF-和TGF-α诱导的核PI3K和PKC-中的作用？激活、核核素磷酸化、OSCC 细胞有丝分裂、存活和侵袭。意义：这些研究将揭示 EGF 配体诱导 OSCC 有丝分裂的新途径，并可能为 OSCC 提供治疗靶点。叙述：口腔鳞状细胞癌是全球第六大常见癌症类型，肿瘤生长失控的机制尚不清楚。这些研究将深入了解表皮生长因子诱导口腔鳞状细胞癌生长的重要机制。了解这些机制将为开发控制口腔鳞状细胞癌的新治疗方案带来新的分子靶点的可能性。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Phospholipase C-gamma1 is required for the epidermal growth factor receptor-induced squamous cell carcinoma cell mitogenesis.

表皮生长因子受体诱导的鳞状细胞癌细胞有丝分裂需要磷脂酶 C-gamma1。

DOI：
10.1016/j.bbrc.2010.05.103
发表时间：
2010-06-25
期刊：
Biochemical and biophysical research communications
影响因子：
3.1
作者：
Xie, Zhongjian;Chen, Ying;Liao, Er-Yuan;Jiang, Yi;Liu, Fu-You;Pennypacker, Sally D.
通讯作者：
Pennypacker, Sally D.

Two distinct mechanisms by which phospholipase C-γ1 mediates epidermal growth factor-induced keratinocyte migration and proliferation.

磷脂酶 C-γ1 介导表皮生长因子诱导的角质形成细胞迁移和增殖的两种不同机制。

DOI：
10.1016/j.jdermsci.2012.06.002
发表时间：
2012-09-01
期刊：
Journal of dermatological science
影响因子：
4.6
作者：
Jian Peng;Liyan Liao;Ying Chen;S. Pennypacker;X. Gao;Shengqian Zhou;Zhongjian Xie
通讯作者：
Zhongjian Xie

PIKE mediates EGFR proliferative signaling in squamous cell carcinoma cells.

PIKE 介导鳞状细胞癌细胞中的 EGFR 增殖信号传导。