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Protooncogene TCL1b functions as an Akt kinase co-activator that exhibits oncogenic potency in vivo

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Title: Protooncogene TCL1b functions as an Akt kinase co-activator that exhibits oncogenic potency in vivo
Authors: Hashimoto, M. Browse this author
Suizu, F. Browse this author
Tokuyama, W. Browse this author
Noguchi, H. Browse this author
Hirata, N. Browse this author
Matsuda-Lennikov, M Browse this author
Edamura, T. Browse this author
Masuzawa, M. Browse this author
Gotoh, N. Browse this author
Tanaka, S. Browse this author
Noguchi, M. Browse this author →KAKEN DB
Keywords: protooncogene TCL1b
transgenic mice
Issue Date: 16-Sep-2013
Publisher: Nature Publishing Group
Journal Title: Oncogenesis
Volume: 2
Issue: 9
Start Page: e70
Publisher DOI: 10.1038/oncsis.2013.30
PMID: 24042734
Abstract: 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 b-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 antiphospho- 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.
Type: article
Appears in Collections:遺伝子病制御研究所 (Institute for Genetic Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 野口 昌幸

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