Roles of XB130, a novel adaptor protein, in cancer.
Roles of XB130, a novel adaptor protein, in cancer.
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DOI：
10.1186/2043-9113-1-10
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发表时间：
2011-03-17
期刊：
影响因子：
--
通讯作者：
Liu M
中科院分区：
文献类型：
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作者：
Shiozaki A;Liu M
衔接子蛋白具有多模块结构，可参与多种细胞功能的调节。在肌动蛋白丝相关蛋白的分子克隆过程中，我们发现了一个新的接头蛋白，命名为XB 130。人xb 130基因定位于染色体10q25.3，编码一个818个氨基酸的蛋白质。XB 130的N-末端区域包括几个酪氨酸磷酸化位点和一个富含脯氨酸的序列，它们可能分别与含Src同源性2和3结构域的蛋白相互作用。我们的研究确实暗示了XB 130作为酪氨酸激酶介导的信号传导的可能底物和调节剂。用小干扰RNA下调内源性XB 130可降低人肺上皮细胞中c-Src活性、IL-8产生和Akt磷酸化。此外，XB 130结合磷脂酰肌醇-3-激酶的p85α亚基，随后通过甲状腺癌细胞中的RET/PTC介导信号传导。使用小干扰RNA敲低XB 130抑制G1-S期进展，诱导自发凋亡，并增强内在和外在凋亡刺激诱导的人肺癌和甲状腺癌细胞死亡。XB 130短发夹状RNA稳定转染的人甲状腺癌细胞在裸鼠体内形成的肿瘤的生长显著减少，细胞增殖减少，凋亡增加。此外，XB 130对片状F-肌动蛋白网络具有高亲和力，并参与癌细胞的运动性和侵袭性。基因表达谱分析显示，在转染XB 130短发夹状RNA的甲状腺癌细胞中，有246个基因发生了显著变化。其中，57个基因与细胞增殖或存活有关，包括许多转录调控因子。通路分析显示，与XB 130相关的疾病中，排在首位的是癌症，排在首位的分子和细胞功能是细胞生长和增殖以及细胞周期。这些观察结果表明，XB 130的表达可能影响各种癌细胞的细胞增殖、存活、运动和侵袭。对这些机制的深入理解可能会导致发现XB 130作为肿瘤发展的重要介质和癌症的新治疗靶点。
Adaptor proteins, with multi-modular structures, can participate in the regulation of various cellular functions. During molecular cloning process of actin filament associated protein, we have discovered a novel adaptor protein, referred to as XB130. The human xb130 gene is localized on chromosome 10q25.3, and encodes an 818 amino acid protein. The N-terminal region of XB130 includes several tyrosine phosphorylation sites and a proline-rich sequence that might interact with Src homology 2 and 3 domain-containing proteins, respectively. Our studies have indeed implicated XB130 as a likely substrate and regulator of tyrosine kinase-mediated signaling. Down-regulation of endogenous XB130 with small interfering RNA reduced c-Src activity, IL-8 production and phosphorylation of Akt in human lung epithelial cells. Further, XB130 binds the p85α subunit of phosphatidyl-inositol-3-kinase and subsequently mediates signaling through RET/PTC in thyroid cancer cells. Knockdown of XB130 using small interfering RNA inhibited G1-S phase progression, induced spontaneous apoptosis and enhanced intrinsic and extrinsic apoptotic stimulus-induced cell death in human lung and thyroid cancer cells. Growth of tumors in nude mice formed from XB130 short hairpin RNA stably transfected human thyroid cancer cells were significantly reduced, with decreased cell proliferation and increased apoptosis. Further, XB130 has a high affinity to lamellipodial F-actin meshwork and is involved in the motility and invasiveness of cancer cells. Gene expression profiling identified 246 genes significantly changed in XB130 short hairpin RNA transfected thyroid cancer cells. Among them, 57 genes are related to cell proliferation or survival, including many transcription regulators. Pathway analysis showed that the top ranked disease related to XB130 is Cancer, and the top molecular and cellular functions are Cellular Growth and Proliferation, and Cell Cycle. These observations suggest that the expression of XB130 may affect cell proliferation, survival, motility and invasion in various cancer cells. A deeper understanding of these mechanisms may lead to the discovery of XB130 as an important mediator in tumor development and as a novel therapeutic target for cancer.