Cooperation of NF-kappaB2/p100 activation and the PDZ domain binding motif signal in human T-cell leukemia virus type 1 (HTLV-1) Tax1 but not HTLV-2 Tax2 is crucial for interleukin-2-independent growth transformation of a T-cell line.
Human T-cell leukemia virus type 1 (HTLV-1) but not HTLV-2 is associated with adult T-cell leukemia, and the distinct pathogenicity of these two closely related viruses is thought to stem from the distinct biological functions of the respective transforming proteins, HTLV-1 Tax1 and HTLV-2 Tax2. In this study, we demonstrate that Tax1 but not Tax2 interacts with NF-kappaB2/p100 and activates it by inducing the cleavage of p100 into the active transcription factor p52. Using RNA interference methods, we further show that NF-kappaB2/p100 is required for the transformation induced by Tax1, as determined by the ability to convert a T-cell line (CTLL-2) from interleukin-2 (IL-2)-dependent to -independent growth. While Tax2 shows a reduced transforming activity relative to Tax1, Tax2 fused with a PDZ domain binding motif (PBM) present only in Tax1 shows transforming activity equivalent to that of Tax1 in CTLL-2 cells expressing an inducer of p52 processing. These results reveal that the activation of NF-kappaB2/p100 plays a crucial role in the Tax1-mediated transformation of T cells and that NF-kappaB2/p100 activation and PBM function are both responsible for the augmented transforming activity of Tax1 relative to Tax2, thus suggesting that these Tax1-specific functions play crucial roles in HTLV-1 leukemogenesis.
Higuchi
Masaya
M
Division of Virology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-Dori, Niigata 951-8510, Japan. mhiguchi@med.niigata-u.ac.jp
Tsubata
Chikako
C
Kondo
Rie
R
Yoshida
Sakiko
S
Takahashi
Masahiko
M
Oie
Masayasu
M
Tanaka
Yuetsu
Y
Mahieux
Renaud
R
Matsuoka
Masao
M
Fujii
Masahiro
M
D020816:Amino Acid Motifs; D000818:Animals; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral; D016356:Gene Products, tax / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism*; D015367:Human T-lymphotropic virus 2 / Q000378:metabolism*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism*; D007938:Leukemia / Q000473:pathology* / Q000821:virology; D051379:Mice; D052003:NF-kappa B p52 Subunit / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D013601:T-Lymphocytes / Q000378:metabolism*
D016356:Gene Products, tax; D007376:Interleukin-2; D052003:NF-kappa B p52 Subunit; C498206:NFKB2 protein, human
J Virol. 1996 Aug;70(8):5194-202
8764028
Virology. 1995 Feb 1;206(2):1066-74
7856081
Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11612-6
9326658
J Virol. 1999 Feb;73(2):1271-7
9882331
J Virol. 1999 Jun;73(6):4856-65
10233947
Blood. 1999 Oct 15;94(8):2862-70
10515890
Virology. 2005 Feb 5;332(1):249-57
15661157
Retrovirology. 2005;2:27
15854229
Retrovirology. 2005;2:16
15743528
Retrovirology. 2005;2:29
15876358
J Virol. 2005 Sep;79(18):11925-34
16140768
Retrovirology. 2005;2:46
16042787
Oncogene. 2005 Sep 5;24(39):5952-64
16155602
Oncogene. 2005 Sep 5;24(39):5965-75
16155603
Oncogene. 2005 Sep 5;24(39):5976-85
16155604
Oncogene. 2005 Sep 5;24(39):5996-6004
16155606
Blood. 2006 Mar 1;107(5):1980-8
16263794
J Virol. 2006 Jun;80(11):5301-7
16699010
Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9220-5
16751281
Biochem Pharmacol. 2006 Oct 30;72(9):1161-79
16970925
Retrovirology. 2006;3:71
17042961
Front Biosci. 2007;12:1496-507
17127397
Retrovirology. 2006;3:88
17140451
Oncogene. 1999 Oct 28;18(44):5967-72
10557085
J Virol. 2000 Mar;74(6):2655-62
10684280
Virology. 2001 Jan 5;279(1):38-46
11145887
Mol Cell. 2001 Feb;7(2):401-9
11239468
EMBO J. 2001 Dec 3;20(23):6805-15
11726516
Oncogene. 2003 Oct 23;22(48):7557-69
14576817
J Biol Chem. 2003 Nov 21;278(47):46565-75
12968033
J Biol Chem. 2003 Dec 19;278(51):51134-42
14532284
Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):141-6
14691250
Virology. 2004 Jan 5;318(1):327-36
14972558
Virology. 2004 Mar 1;320(1):52-62
15003862
Proc Natl Acad Sci U S A. 2004 Jun 22;101(25):9399-404
15190178
J Biol Chem. 2004 Oct 8;279(41):43307-20
15269214
Cell. 1987 Jan 30;48(2):343-50
3026643
Cell. 1987 Apr 10;49(1):47-56
3030566
J Virol. 1992 Jul;66(7):4570-5
1351105
Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):7070-4
1386673
Genes Dev. 1992 Nov;6(11):2066-76
1427072
J Virol. 1993 Mar;67(3):1211-7
8437212
Oncogene. 1994 Mar;9(3):841-52
8108127
Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6670-5
9192623