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Insulin-like growth factor binding protein-2: Contributions of the C-terminal domain to IGF binding and role in oral and oropharyngeal squamous cell carcinoma.

机译：胰岛素样生长因子结合蛋白2：C端结构域对IGF结合的贡献以及在口腔和口咽鳞状细胞癌中的作用。

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The insulin-like growth factor-1 receptor (IGF-1R) mediates the growth activities of the insulin-like growth factors (IGFs). The IGFs bind with high affinity to the IGF binding proteins (IGFBPs), which effectively inhibit IGF-1R activation due to their greater affinity for the IGFs than that of the IGF-1R. Thus, the IGFBPs are IGF antagonists. Several molecular markers have been associated with oral and oropharyngeal squamous cell carcinoma (OSCC), yet the prognostic and therapeutic relevance of these markers are absent. A component of the IGF system may be a molecular marker of OSCC, and thus may be exploited to develop therapeutic and preventative agents. The objectives of this study were to determine the contributions of the C-terminal domain of IGFBP-2 to IGF binding and to establish a role for IGF-1R signaling in enhancing OSCC tumorigenicity. To ascertain the role of the C-terminus of IGFBP-2 in IGF binding, we selectively cleaved IGFBP-2 with BNPS-skatole, expressed IGFBP-2 truncation mutants (IGFBP-21-248, IGFBP-21-190, and IGFBP-2249-289) and tested their IGF-1 binding activity. Using 6His·IGFBP-2 (EC50 0.76 nM) as the control, recombinant IGFPB-21-190 (EC50 9.2 nM) had similar IGF binding properties to IGFBP-21-248 (EC50 7 nM) with lower efficacy in blocking IGF-binding to the receptor, suggesting that proximal residues (191-248) contribute to blocking IGF-1 from binding to the IGF-1R. The kinetic studies indicated that distal residues (249-289) provide stability to the IGFBP-2/IGF-1 complex accounting for the slower dissociation rates observed for IGFBP-2 versus IGFBP-2 1-248. Furthermore, expression of IGF system components in OSCC cell lines was characterized and functional studies were performed. The level of IGF-1R expression was greater (55,000-89,700 R/cell) than the accepted normal physiologic range (15,000-30,000 R/cell). The cells expressed IGF-1 and -2 and IGFBP-2, -3 and -5 and underwent a 2.5-fold increase in cell number upon addition of 1 nM IGF-1. In conclusion, both the distal and proximal regions of the C-terminal domain of IGFBP-2 provide stability and are necessary for inhibiting IGF-1 binding to the IGF-1R. The OSCC analysis exhibits the prerequisites for demonstrating the dysregulation of the IGF system in contributing to the progression of this cancer.

机译：胰岛素样生长因子-1受体（IGF-1R）介导胰岛素样生长因子（IGFs）的生长活性。 IGF与IGF结合蛋白（IGFBP）具有高亲和力结合，由于它们对IGF的亲和力高于IGF-1R，IGF结合蛋白（IGFBP）有效抑制了IGF-1R的活化。因此，IGFBP是IGF拮抗剂。几种分子标记物已与口腔和口咽鳞状细胞癌（OSCC）相关联，但尚缺乏这些标记物的预后和治疗意义。 IGF系统的组成部分可以是OSCC的分子标记，因此可以用于开发治疗剂和预防剂。这项研究的目的是确定IGFBP-2的C末端域对IGF结合的贡献，并确定IGF-1R信号传导在增强OSCC致瘤性中的作用。为了确定IGFBP-2的C末端在IGF结合中的作用，我们用BNPS粪便选择性切割了IGFBP-2，表达了IGFBP-2截短突变体（IGFBP-21-248，IGFBP-21-190和IGFBP- 2249-289），并测试了它们的IGF-1结合活性。以6His·IGFBP-2（EC50 0.76 nM）为对照，重组IGFBP-21-190（EC50 9.2 nM）具有与IGFBP-21-248（EC50 7 nM）类似的IGF结合特性，但阻断IGF结合的功效较低提示受体附近的残基（191-248）有助于阻断IGF-1与IGF-1R的结合。动力学研究表明，远端残基（249-289）为IGFBP-2 / IGF-1复合物提供了稳定性，这说明了IGFBP-2相对于IGFBP-2 1-248观察到的解离速率较慢。此外，表征了IGC系统组分在OSCC细胞系中的表达并进行了功能研究。 IGF-1R表达水平（55,000-89,700 R /细胞）大于公认的正常生理范围（15,000-30,000 R /细胞）。细胞表达IGF-1和-2以及IGFBP-2，-3和-5，并且在添加1nM IGF-1后细胞数增加了2.5倍。总之，IGFBP-2 C末端结构域的远端和近端区域均提供稳定性，对于抑制IGF-1与IGF-1R的结合是必需的。 OSCC分析显示了证明IGF系统失调导致该癌症进展的先决条件。

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作者
Kibbey, Megan Marie.;
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作者单位

Medical University of South Carolina.;

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授予单位 Medical University of South Carolina.;
学科 Biology Molecular.
学位 Ph.D.
年度 2008
页码 199 p.
总页数 199
原文格式 PDF
正文语种 eng
中图分类分子遗传学;
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1. Insulin-like growth factor binding protein-2: contributions of the C-terminal domain to insulin-like growth factor-1 binding. [J] . Kibbey MM, Jameson MJ, Eaton EM, Molecular pharmacology. . 2006,第3期

机译：胰岛素样生长因子结合蛋白2：C末端域对胰岛素样生长因子1结合的贡献。
2. Structure, dynamics and heparin binding of the C-terminal domain of insulin-like growth factor-binding protein-2 (IGFBP-2) [J] . Kuang ZH, Yao SG, Keizer DW, Journal of Molecular Biology . 2006,第4期

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3. Cooperativity of the N- and C-Terminal Domains of Insulin-like Growth Factor (IGF) Binding Protein 2 in IGF Binding [J] . Zhihe Kuang, Shenggen Yao, Kerrie A. McNeil Biochemistry . 2007,第48期

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5. The role of insulin-like growth factor binding protein-3 (IGFBP-3) in the proliferation and differentiation of L6 myogenic cells and porcine embryonic myogenic cells (PEMC). [D] . Xi, Gang. 2005

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6. The Coordinate Cellular Response to Insulin-like Growth Factor-I (IGF-I) and Insulin-like Growth Factor-binding Protein-2 (IGFBP-2) Is Regulated through Vimentin Binding to Receptor Tyrosine Phosphatase β (RPTPβ) [O] . Xinchun Shen, Gang Xi, Christine Wai, 2015

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8. Role of Insulin-Like Growth Factor (IGF) Binding Proteins (IGFBPs) in IGF-Mediated Tumorigenicity [R] . Harbeson, C. E. , Rosenzweig, S. A. 2003

机译：胰岛素样生长因子（IGF）结合蛋白（IGFBps）在IGF介导的致瘤性中的作用

Insulin-like growth factor binding protein-2: Contributions of the C-terminal domain to IGF binding and role in oral and oropharyngeal squamous cell carcinoma.

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