title: Protooncogene TCL1b functions as an Akt kinase co-activator that exhibits oncogenic potency in vivo.
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 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.
authors.affiliation: Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Hashimoto
authors.forename: F
authors.initials: F
authors.lastname: Suizu
authors.forename: W
authors.initials: W
authors.lastname: Tokuyama
authors.forename: H
authors.initials: H
authors.lastname: Noguchi
authors.forename: N
authors.initials: N
authors.lastname: Hirata
authors.forename: M
authors.initials: M
authors.lastname: Matsuda-Lennikov
authors.forename: T
authors.initials: T
authors.lastname: Edamura
authors.forename: M
authors.initials: M
authors.lastname: Masuzawa
authors.forename: N
authors.initials: N
authors.lastname: Gotoh
authors.forename: S
authors.initials: S
authors.lastname: Tanaka
authors.forename: M
authors.initials: M
authors.lastname: Noguchi
references.citation: Cancer Cell. 2006 Aug;10(2):159-70
references.pmid: 16904613
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14950-5
references.pmid: 9843996
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 4;102(1):128-33
references.pmid: 15611473
references.citation: Nucleic Acids Res. 2010 Jan;38(Database issue):D355-60
references.pmid: 19880382
references.citation: FEBS Lett. 2003 Jul 3;546(1):108-12
references.pmid: 12829245
references.citation: J Biol Chem. 2002 Feb 1;277(5):3743-51
references.pmid: 11707444
references.citation: Gene. 1989 Jul 15;79(2):269-77
references.pmid: 2551778
references.citation: J Biol Chem. 1996 Dec 6;271(49):31372-8
references.pmid: 8940145
references.citation: Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):3690-4
references.pmid: 11274386
references.citation: Science. 2005 Feb 18;307(5712):1098-101
references.pmid: 15718470
references.citation: J Biol Chem. 2004 Dec 17;279(51):53407-18
references.pmid: 15459205
references.citation: FASEB J. 2007 Aug;21(10):2273-84
references.pmid: 17360849
references.citation: Am J Pathol. 2010 May;176(5):2139-49
references.pmid: 20228224
references.citation: Mol Cell Biol. 2002 Mar;22(5):1513-25
references.pmid: 11839817
references.citation: Science. 1998 Jan 30;279(5351):710-4
references.pmid: 9445477
references.citation: J Dermatol Sci. 2007 Oct;48(1):64-6
references.pmid: 17720094
references.citation: Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3028-33
references.pmid: 10716693
references.citation: Cell. 1999 Mar 19;96(6):857-68
references.pmid: 10102273
references.citation: Blood. 1998 Jul 15;92(2):368-73
references.pmid: 9657733
references.citation: Science. 2002 May 31;296(5573):1655-7
references.pmid: 12040186
references.citation: Nucleic Acids Res. 2012 Jan;40(Database issue):D109-14
references.pmid: 22080510
references.citation: Mol Cell. 2000 Aug;6(2):395-407
references.pmid: 10983986
references.citation: Science. 1997 Jun 20;276(5320):1848-50
references.pmid: 9188528
references.citation: Trends Immunol. 2003 Mar;24(3):104-8
references.pmid: 12615201
references.citation: Postepy Hig Med Dosw (Online). 2009 Feb 24;63:73-91
references.pmid: 19252466
references.citation: Nat Genet. 2000 May;25(1):25-9
references.pmid: 10802651
references.citation: Cancer Cell. 2003 Oct;4(4):257-62
references.pmid: 14585353
references.citation: Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9809-14
references.pmid: 10449776
references.citation: Dev Cell. 2009 Dec;17(6):800-10
references.pmid: 20059950
references.citation: Oncogene. 2005 Nov 14;24(50):7455-64
references.pmid: 16288292
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14392-7
references.pmid: 12381789
references.citation: Nat Rev Cancer. 2005 Aug;5(8):640-8
references.pmid: 16056259
references.citation: Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1475-9
references.pmid: 16432179
references.citation: Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11712-7
references.pmid: 12181493
references.citation: Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):2949-51
references.pmid: 10077617
references.citation: Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3885-9
references.pmid: 9520462
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14863-8
references.pmid: 9843981
references.citation: Arch Dermatol. 2007 Apr;143(4):504-6
references.pmid: 17438183
references.citation: J Biol Chem. 2004 Aug 20;279(34):35890-902
references.pmid: 15169787
references.citation: Blood. 2009 Nov 12;114(20):4469-76
references.pmid: 19755673
references.citation: Lancet Oncol. 2010 Oct;11(10):983-91
references.pmid: 20537949
references.citation: Ann Surg. 2010 Jun;251(6):1098-106
references.pmid: 20485141
references.citation: Cell. 2007 Jun 29;129(7):1261-74
references.pmid: 17604717
references.citation: Nat Rev Mol Cell Biol. 2011 Jan;12(1):21-35
references.pmid: 21157483
references.citation: Nature. 1999 Sep 2;401(6748):82-5
references.pmid: 10485710
references.citation: J Biomol NMR. 2004 Feb;28(2):137-55
references.pmid: 14755158
references.citation: Cancer Res. 2006 Jan 15;66(2):915-20
references.pmid: 16424025
references.citation: Toxicol Sci. 2009 Sep;111(1):4-18
references.pmid: 19525443
references.citation: Proc Natl Acad Sci U S A. 1999 Dec 7;96(25):14418-23
references.pmid: 10588720
references.citation: Oncogene. 1993 Sep;8(9):2475-83
references.pmid: 8361760
references.citation: Oncogene. 2001 Jul 19;20(32):4419-23
references.pmid: 11466625
references.citation: Histopathology. 2010 Jul;57(1):152-7
references.pmid: 20553335
references.citation: Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12530-4
references.pmid: 7809072
references.citation: Proc Natl Acad Sci U S A. 2009 Apr 14;106(15):6250-5
references.pmid: 19332800