Shiozaki Atsushi, Liu Mingyao
Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan.
J Clin Bioinforma. 2011 Mar 17;1(1):10. doi: 10.1186/2043-9113-1-10.
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.
衔接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，我们发现了一种新型衔接蛋白，称为XB130。人类xb130基因定位于染色体10q25.3，编码一个含818个氨基酸的蛋白质。XB130的N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2和3结构域的蛋白相互作用。我们的研究确实表明XB130可能是酪氨酸激酶介导信号传导的底物和调节因子。用小干扰RNA下调内源性XB130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，XB130结合磷脂酰肌醇-3-激酶的p85α亚基，随后在甲状腺癌细胞中介导通过RET/PTC的信号传导。使用小干扰RNA敲低XB130可抑制人肺癌和甲状腺癌细胞的G1-S期进程，诱导自发凋亡，并增强内在和外在凋亡刺激诱导的细胞死亡。由XB130短发夹RNA稳定转染的人甲状腺癌细胞在裸鼠中形成的肿瘤生长明显减少，细胞增殖减少，凋亡增加。此外，XB130与片状伪足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。基因表达谱分析确定了在XB130短发夹RNA转染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相关，包括许多转录调节因子。通路分析表明，与XB130相关的排名最靠前的疾病是癌症，排名最靠前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，XB130的表达可能影响各种癌细胞的增殖、存活、运动性和侵袭性。对这些机制的更深入了解可能会导致发现XB130是肿瘤发展中的重要介质和癌症的新型治疗靶点。
