title: ERK and JNK activation is essential for oncogenic transformation by v-Rel.
abstract: v-Rel is the acutely oncogenic member of the NF-κB family of transcription factors. Infection with retroviruses expressing v-Rel rapidly induces fatal lymphomas in birds and transforms primary lymphocytes and fibroblasts in vitro. We have previously shown that AP-1 transcriptional activity contributes to v-Rel-mediated transformation. Although v-Rel increases the expression of these factors, their activity may also be induced through phosphorylation by the mitogen-activated protein kinases (MAPKs). The expression of v-Rel results in the strong and sustained activation of the ERK and JNK MAPK pathways. This induction is critical for the v-Rel-transformed phenotype, as suppression of MAPK activity with chemical inhibitors or small interfering RNA severely impairs colony formation of v-Rel-transformed lymphoid cell lines. However, signaling must be maintained within an optimal range in these cells, as strong additional activation of either pathway beyond the levels induced by v-Rel through the expression of constitutively active MAPK proteins attenuates the transformed phenotype. MAPK signaling also has an important role in the initial transformation of primary spleen cells by v-Rel, although distinct requirements for MAPK activity at different stages of v-Rel-mediated transformation were identified. We also show that the ability of v-Rel to induce MAPK signaling more strongly than c-Rel contributes to its greater oncogenicity.
authors.affiliation: Section of Molecular Genetics and Microbiology, Institute of Cellular and Molecular Biology, University of Texas at Austin, Austin, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Kralova
authors.forename: J I
authors.initials: JI
authors.lastname: Sheely
authors.forename: A S
authors.initials: AS
authors.lastname: Liss
authors.forename: H R
authors.initials: HR
authors.lastname: Bose
mesh_terms: D000818:Animals; D002460:Cell Line; D002472:Cell Transformation, Viral / Q000235:genetics*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D020573:Genes, rel / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D010641:Phenotype; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases
references.citation: Cancer Res. 2004 Aug 15;64(16):5556-9
references.pmid: 15313890
references.citation: Mol Cell Biol. 1997 Sep;17(9):5598-611
references.pmid: 9271435
references.citation: Environ Health Perspect. 2002 Sep;110(9):865-70
references.pmid: 12204819
references.citation: FASEB J. 2008 Feb;22(2):466-76
references.pmid: 17928366
references.citation: Curr Biol. 1998 Oct 22;8(21):1141-50
references.pmid: 9799732
references.citation: Oncogene. 1997 Jun 19;14(24):2881-97
references.pmid: 9205096
references.citation: Cancer Res. 2008 Feb 1;68(3):808-14
references.pmid: 18245482
references.citation: Cancer Res. 2001 May 15;61(10):3908-12
references.pmid: 11358804
references.citation: Oncogene. 2006 Feb 2;25(5):756-68
references.pmid: 16186799
references.citation: Biochim Biophys Acta. 2007 Aug;1773(8):1263-84
references.pmid: 17126425
references.citation: Trends Immunol. 2004 Jun;25(6):280-8
references.pmid: 15145317
references.citation: Nature. 2001 May 17;411(6835):355-65
references.pmid: 11357143
references.citation: Oncogene. 2007 May 14;26(22):3172-84
references.pmid: 17496914
references.citation: Growth Factors. 2006 Mar;24(1):21-44
references.pmid: 16393692
references.citation: Clin Cancer Res. 2003 Jan;9(1):391-401
references.pmid: 12538493
references.citation: Genes Dev. 2003 Mar 1;17(5):629-37
references.pmid: 12629045
references.citation: Mol Cell Biol. 1998 May;18(5):2997-3009
references.pmid: 9566919
references.citation: Mol Cell Biol. 1997 Sep;17(9):5588-97
references.pmid: 9271434
references.citation: Cancer Genet Cytogenet. 2006 Mar;165(2):151-6
references.pmid: 16527609
references.citation: Oncogene. 2007 May 14;26(22):3279-90
references.pmid: 17496922
references.citation: Cancer Res. 2002 Jun 1;62(11):3257-63
references.pmid: 12036942
references.citation: Mol Cell Biol. 1999 Mar;19(3):1938-49
references.pmid: 10022881
references.citation: Oncogene. 2010 Sep 2;29(35):4925-37
references.pmid: 20562914
references.citation: Oncogene. 1999 Nov 22;18(49):6925-37
references.pmid: 10602467
references.citation: J Biol Chem. 1999 Oct 8;274(41):28966-71
references.pmid: 10506143
references.citation: Science. 1994 Aug 12;265(5174):966-70
references.pmid: 8052857
references.citation: Nat Cell Biol. 2002 May;4(5):E131-6
references.pmid: 11988758
references.citation: Trends Biochem Sci. 2006 May;31(5):268-75
references.pmid: 16603362
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4519-24
references.pmid: 19251651
references.citation: J Invest Dermatol. 2008 Aug;128(8):2003-12
references.pmid: 18323787
references.citation: Genes Dev. 2004 Sep 15;18(18):2195-224
references.pmid: 15371334
references.citation: Cancer Res. 1999 Feb 15;59(4):803-6
references.pmid: 10029066
references.citation: Oncogene. 2006 Oct 30;25(51):6800-16
references.pmid: 17072329
references.citation: Oncogene. 2004 Mar 25;23(13):2275-86
references.pmid: 14755244
references.citation: Oncogene. 1996 May 16;12(10):2193-202
references.pmid: 8668346
references.citation: Mol Carcinog. 2007 Aug;46(8):591-8
references.pmid: 17538955
references.citation: Nature. 2006 May 25;441(7092):431-6
references.pmid: 16724054
references.citation: Oncogene. 2007 May 14;26(22):3100-12
references.pmid: 17496909
references.citation: Hum Gene Ther. 1998 Nov 1;9(16):2401-5
references.pmid: 9829539
references.citation: Oncogene. 2007 Nov 8;26(51):7222-30
references.pmid: 17525747
references.citation: Cancer Res. 2007 Jan 1;67(1):178-85
references.pmid: 17210697
references.citation: Oncogene. 1996 Jun 20;12(12):2595-604
references.pmid: 8700518
references.citation: Oncogene. 1991 Sep;6(9):1491-7
references.pmid: 1923517
references.citation: Mol Cell Biol. 1999 Oct;19(10):6742-53
references.pmid: 10490613
references.citation: J Immunol. 2007 Jun 1;178(11):7097-109
references.pmid: 17513759
references.citation: Oncogene. 2008 May 1;27(20):2801-9
references.pmid: 18193093
references.citation: Bioessays. 2003 Jan;25(1):17-24
references.pmid: 12508278
references.citation: J Biol Chem. 2004 Oct 15;279(42):43861-9
references.pmid: 15284233
references.citation: Oncogene. 2006 Oct 30;25(51):6817-30
references.pmid: 17072330
references.citation: J Exp Clin Cancer Res. 2005 Dec;24(4):505-14
references.pmid: 16471312