Protooncogene TCL1b functions as an Akt kinase co-activator that exhibits oncogenic potency in vivo.
Protooncogene TCL1b functions as an Akt kinase co-activator that exhibits oncogenic potency in vivo.
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DOI：
10.1038/oncsis.2013.30
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发表时间：
2013-09-16
期刊：
影响因子：
6.2
通讯作者：
Noguchi, M.
中科院分区：
文献类型：
--
作者：
Hashimoto, M.;Suizu, F.;Tokuyama, W.;Noguchi, H.;Hirata, N.;Matsuda-Lennikov, M.;Edamura, T.;Masuzawa, M.;Gotoh, N.;Tanaka, S.;Noguchi, M.
原癌基因 T 细胞白血病 1 (TCL1) 与人类 T 细胞幼淋巴细胞白血病 (T-PLL) 相关，与 Akt 相互作用并增强其激酶活性，充当 Akt 激酶共激活剂。 TCL1 原癌基因的两个主要亚型（TCL1 和 TCL1b）彼此相邻地存在于人类染色体 14q.32 上。在人类 T-PLL 中，TCL1 和 TCL1b 均由染色体易位激活。此外，TCL1b转基因小鼠从未被创造出来。因此，尚不清楚TCL1b本身是否独立于TCL1而表现出致癌性。在免疫共沉淀测定中，异位和内源 TCL1b 均与 Akt 相互作用。在体外 Akt 激酶测定中，TCL1b 以剂量和时间依赖性方式增强 Akt 激酶活性。利用多重回归分析、聚类分析、KEGG（京都基因和基因组百科全书）通路图谱、维恩图和基因本体论 (GO) 的生物信息学方法证明，TCL1b 显示出与 Myr-Akt 或 TCL1 相似的高度同源基因诱导特征。 TCL1b 在体外集落转化试验中表现出致癌性。此外，β-肌动蛋白启动子驱动的 TCL1b 转基因小鼠的两个独立品系在肠道上出现了血管肉瘤。血管肉瘤是一种罕见的人类癌症，预后较差。使用免疫组织化学方法，13 份人类血管肉瘤样本中的 11 份抗 TCL1b 和抗磷酸 Akt 抗体均呈阳性染色。一致的是，在各种癌症组织中，146 个样本中的 69 个样本抗 TCL1b 呈阳性染色，其中 46 个样本抗磷酸 Akt 抗体呈阳性染色。此外，基于 TCL1b 结构的抑制剂“TCL1b-Akt-in”在体外激酶测定中抑制 Akt 激酶活性和 PDGF（血小板衍生生长因子）诱导的 Akt 激酶活性，反过来，“TCL1b-Akt-in”抑制肉瘤的细胞增殖。目前的研究表明TCL1b具有致癌性，因此可以作为人类肿瘤疾病的新治疗靶点。
Protooncogene T-cell leukemia 1 (TCL1), which is implicated in human T-cell prolymphocytic leukemia (T-PLL), interacts with Akt and enhances its kinase activity, functioning as an Akt kinase co-activator. Two major isoforms of TCL1 Protooncogenes (TCL1 and TCL1b) are present adjacent to each other on human chromosome 14q.32. In human T-PLL, both TCL1 and TCL1b are activated by chromosomal translocation. Moreover, TCL1b-transgenic mice have never been created. Therefore, it remains unclear whether TCL1b itself, independent of TCL1, exhibits oncogenicity. In co-immunoprecipitation assays, both ectopic and endogenous TCL1b interacted with Akt. In in vitro Akt kinase assays, TCL1b enhanced Akt kinase activity in dose- and time-dependent manners. Bioinformatics approaches utilizing multiregression analysis, cluster analysis, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway mapping, Venn diagrams and Gene Ontology (GO) demonstrated that TCL1b showed highly homologous gene-induction signatures similar to Myr-Akt or TCL1. TCL1b exhibited oncogenicity in in vitro colony-transformation assay. Further, two independent lines of β-actin promoter-driven TCL1b-transgenic mice developed angiosarcoma on the intestinal tract. Angiosarcoma is a rare form of cancer in humans with poor prognosis. Using immunohistochemistry, 11 out of 13 human angiosarcoma samples were positively stained with both anti-TCL1b and anti-phospho-Akt antibodies. Consistently, in various cancer tissues, 69 out of 146 samples were positively stained with anti-TCL1b, out of which 46 were positively stained with anti-phospho-Akt antibodies. Moreover, TCL1b structure-based inhibitor ‘TCL1b-Akt-in' inhibited Akt kinase activity in in vitro kinase assays and PDGF (platelet-derived growth factor)-induced Akt kinase activities—in turn, ‘TCL1b-Akt-in' inhibited cellular proliferation of sarcoma. The current study disclosed TCL1b bears oncogenicity and hence serves as a novel therapeutic target for human neoplastic diseases.
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影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
14.9
作者：
Kanehisa M;Goto S;Sato Y;Furumichi M;Tanabe M
通讯作者：
Tanabe M
影响因子：
20.3
作者：
Gritti, C;Dastot, H;Stern, MH
通讯作者：
Stern, MH
影响因子：
4.8
作者：
Hiromura, M;Okada, F;Noguchi, M
通讯作者：
Noguchi, M
DOI：
10.1073/pnas.0901166106
发表时间：
2009-04-14
影响因子：
11.1
作者：
Gorgun, Gullu;Ramsay, Alan G.;Gribben, John G.
通讯作者：
Gribben, John G.