FRS2-mediated Signals in Prostatic Tumorigenesis and Development

FRS2 介导的信号在前列腺肿瘤发生和发展中的作用

• 批准号: 8433519
• 负责人: FEN WANG
• 金额: $ 23.22万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8433519
• 关键词: Ablation; Adaptor Signaling Protein; Alleles; American; Androgens; Animal Model; Animals; Attenuated; Basal Cell; Biochemical; Biological; Biological Assay; Cancer Diagnostics; Cancer Etiology; Cancer Patient; Cell Line; Cell physiology; Cells; Cessation of life; Data; Development; Dietary Component; Epithelial; Epithelial Cells; FGFR1 gene; FGFR2 gene; FRS2 gene; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Future; Genetically Engineered Mouse; Growth; Health; Healthcare Systems; Homeostasis; In Vitro; Interruption; Life; Life Expectancy; Light; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Methods; Molecular; Morphogenesis; Natural regeneration; Pathway interactions; Phosphotransferases; Play; Population; Prevention strategy; Preventive Intervention; Process; Prostate; Prostate Cancer therapy; Prostatic; Prostatic Neoplasms; Prostatic hypertrophy; Protein Isoforms; Protein Tyrosine Kinase; Quality of life; Receptor Signaling; Regulation; Role; Second Primary Cancers; Signal Pathway; Signal Transduction; Societies; Staging; Stem cells; Structure; Systems Analysis; Technology; Testing; Tissues; Tumor Escape; Tumorigenicity; base; cancer initiation; design; improved; in vivo; male; mouse model; neoplastic cell; novel; nutrition; precursor cell; prevent; prostate carcinogenesis; receptor; tool; tumor; tumor initiation; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The pleiotropic fibroblast growth factors (FGF) control a broad spectrum of cellular processes, including prostate development, function, and homeostasis, by activating the four highly homologous FGF receptor (FGFR) transmembrane tyrosine kinases. Aberrant expression and activation of the FGF signaling axis are often found associated with prostatic tumor development and progression. FRS2? is an adaptor protein linking the FGFR kinases to downstream signaling targets, which is differentially phosphorylated by the FGFR1 and FGFR2 kinases in prostate epithelial cells. FRS2? is dynamically expressed in developing prostates, which is associated with prostatic branching morphogenesis, androgen-induced regeneration, and tumorigenesis. The project is to test the hypothesis that FGFR isoform-specific activation of FRS2?-mediated signals play important roles in regulating proliferation and differentiation of precursor cells for prostatic epithelial cells during development and regeneration, and aberrant activation of FRS2?-mediated signaling contributes to prostatic tumorigenesis, which was formulated based on our recent findings. Efforts will be focused on using genetically engineered mouse as well as molecular biological, cell biological, and biochemical technologies to understand how aberrant cell signaling contributes to prostate tumor initiation and progression. The specific aims are to characterize the structural domain of FRS2? that are important for mediating FGFR signals; to characterize the role of FRS2 in prostatic development and tissue homeostasis; and to investigate how aberrant signals mediated by FRS2? contribute to prostatic tumorigenesis and tumor progression. The objective is to understand how FGFR elicits receptor specific signals at the substrate level and the roles of FRS2?-mediated signals in prostatic development, tissue homeostasis, and tumorigenesis. Understanding the role of FGFR signals in prostatic development and tumorigenesis will shed new light on designing new strategies for prevention and interception of prostate cancer initiation and progression in the future. Animal models developed in the project will provide a useful tool not only for further studying FGFR signals in prostate cancer initiation and progression, but also for assessing the role of nutrition and active dietary components on prevention, intervention, and interruption on prostate tumor progression.

描述（由申请人提供）：通过激活四种高度同源的FGF受体（FGFR）跨膜酪氨酸酪氨酸激酶，通过激活四种高度同源的FGF受体（FGFR）来控制一系列细胞过程，包括前列腺发育，功能和稳态，包括多种细胞过程。经常发现FGF信号轴的异常表达和激活与前列腺肿瘤的发展和进展有关。 FRS2？是一种将FGFR激酶与下游信号靶标连接起来的衔接蛋白，该靶标被前列腺上皮细胞中的FGFR1和FGFR2激酶差异化。 FRS2？在发育中的前列腺中动态表达，这与前列腺分支形态发生，雄激素诱导的再生和肿瘤发生有关。该项目是为了测试以下假设：FRS2？介导的信号的FGFR特异性激活在调节前列腺上皮细胞的增殖和分化过程中起着重要作用，在发育和再生过程中，前列腺上皮细胞以及FRS2的异常激活？受FRS的激活？受到前列性肿瘤的影响，有助于使用前列腺肿瘤，以我们最近的形式进行了形式。努力将集中于使用基因工程小鼠以及分子生物学，细胞生物学和生化技术，以了解异常细胞信号如何有助于前列腺肿瘤的启动和进展。具体目的是表征FRS2的结构域？对于中介FGFR信号很重要；表征FRS2在前列腺发育和组织稳态中的作用；并研究FRS2介导的异常信号？有助于前列腺肿瘤发生和肿瘤进展。目的是了解FGFR如何在底物水平上引起受体特定信号以及FRS2？介导的信号在前列腺发育，组织稳态和肿瘤发生中的作用。了解FGFR信号在前列腺发育和肿瘤发生中的作用将为预防和拦截前列腺癌的启动和进展的新策略提供新的启示。该项目中开发的动物模型将不仅为进一步研究前列腺癌开始和进展的FGFR信号提供有用的工具，还可以评估营养和积极饮食成分在预防，干预和中断前列腺肿瘤进展中的作用。

项目成果

Aberrant expression of Cks1 and Cks2 contributes to prostate tumorigenesis by promoting proliferation and inhibiting programmed cell death.

• DOI: 10.1002/ijc.23548
• 发表时间: 2008-08-01
• 期刊: INTERNATIONAL JOURNAL OF CANCER
• 影响因子: 6.4
• 作者: Lan, Yongsheng;Zhang, Yongyou;Wang, Jianghua;Lin, Chunhong;Ittmann, Michael M.;Wang, Fen
• 通讯作者: Wang, Fen

FGFR2 in the dental epithelium is essential for development and maintenance of the maxillary cervical loop, a stem cell niche in mouse incisors.

• DOI: 10.1002/dvdy.21778
• 发表时间: 2009-02
• 期刊: DEVELOPMENTAL DYNAMICS
• 影响因子: 2.5
• 作者: Lin, Yongshun;Cheng, Yi-Shing Lisa;Qin, Chunlin;Lin, Chunhong;D'Souza, Rena;Wang, Fen
• 通讯作者: Wang, Fen

Clinical significance of overexpressed cyclin-dependent kinase subunits 1 and 2 in esophageal carcinoma.

食管癌中过度表达的细胞周期蛋白依赖性激酶亚基 1 和 2 的临床意义。

• DOI: 10.1111/dote.12013
• 发表时间: 2013-09
• 期刊: Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus
• 作者: Wang JJ;Fang ZX;Ye HM;You P;Cai MJ;Duan HB;Wang F;Zhang ZY
• 通讯作者: Zhang ZY

Fibroblast growth factor receptor 1 (FGFR1) tyrosine phosphorylation regulates binding of FGFR substrate 2alpha (FRS2alpha) but not FRS2 to the receptor.

• DOI: 10.1210/me.2007-0140
• 发表时间: 2008
• 期刊: Molecular endocrinology
• 作者: Yongyou Zhang;K. Mckeehan;Yongshun Lin;Jue Zhang;Fen Wang

Plasma levels of microRNA-24, microRNA-320a, and microRNA-423-5p are potential biomarkers for colorectal carcinoma.

microRNA-24、microRNA-320a 和 microRNA-423-5p 的血浆水平是结直肠癌的潜在生物标志物

• DOI: 10.1186/s13046-015-0198-6
• 发表时间: 2015-08-22
• 期刊: Journal of experimental & clinical cancer research : CR
• 作者: Fang Z;Tang J;Bai Y;Lin H;You H;Jin H;Lin L;You P;Li J;Dai Z;Liang X;Su Y;Hu Q;Wang F;Zhang ZY
• 通讯作者: Zhang ZY