Down-regulation of SHP1 and up-regulation of negative regulators of JAK/STAT signaling in HTLV-1 transformed cell lines and freshly transformed human peripheral blood CD4+ T-cells

被引:21
作者
Cheng, JH
Zhang, DS
Zhou, CH
Marasco, WA
机构
[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA
关键词
signal transductiom; adult T-cell leukemia; retrovirus; cancer; IL-2; receptor;
D O I
10.1016/S0145-2126(03)00158-9
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Adult T-cell leukemia (ATL) is an aggressive malignancy that is associated with human T-cell lymphotropic virus 1 (HTLV-1) infection. HTLV-1 transformed T-cell lines and fresh ATL cells are characterized by constitutive activation of the interleukin-2 receptor (IL-2R) signaling pathway however, the mechanism(s) responsible for constitutive IL-2R activation are unknown. To further examine the cause of this signaling pathway deregulation, we measured mRNA and protein expression levels by real-time PCR and Western blots, respectively, of four negative regulators of the IL-2R signaling pathway including src homology 2 (SH2)-containing phosphatase (SHP]), cytokine-inducible (CIS) SH2-containing protein, suppressor of cytokine signaling-1 (SOCS1) and protein inhibitor of activated signal transducer and activator of transcription 3 (STAT3) (PIAS3) in six HTLV-1 negative and seven HTLV-1 positive T-cell leukemia lines. The activation status of the JAK/STAT pathway was also examined. SHP1 mRNA and protein expression levels were selectively down regulated in all HTLV-1-infected transformed cell lines, while CIS, SOCS 1, and PIAS3 protein expression were markedly but variably upregulated and the cells showed evidence of constitutive STAT3 activation. In acutely HTLV-1 infected primary CD4(+) T-cells there was a gradual loss of SHP1 expression over 10 weeks in culture which correlated with progression from immortalization to transformation and loss of IL-2 dependence for growth. Two transformed cell lines that were established following HTLV-1 infection showed loss of SHP1 expression and overexpression of CIS, SOCS1, PIAS3. However, this overexpression was not adequate to block constitutive activation of the JAK/STAT pathway. Thus, multiple levels of IL-2 receptor signal deregulation are found in HTLV-1 transformed cells, which may be a result of early loss of SHP1 expression. (C) 2003 Elsevier Ltd. All rights reserved.
引用
收藏
页码:71 / 82
页数:12
相关论文
共 70 条
[41]   CONSTITUTIVELY ACTIVATED JAK-STAT PATHWAY IN T-CELLS TRANSFORMED WITH HTLV-I [J].
MIGONE, TS ;
LIN, JX ;
CERESETO, A ;
MULLOY, JC ;
O'SHEA, JJ ;
FRANCHINI, G ;
LEONARD, WJ .
SCIENCE, 1995, 269 (5220) :79-81
[42]   The deubiquitinating enzyme DUB-2 prolongs cytokine-induced signal transducers and activators of transcription activation and suppresses apoptosis following cytokine withdrawal [J].
Migone, TS ;
Humbert, M ;
Rascle, A ;
Sanden, D ;
D'Andrea, A ;
Johnston, JA .
BLOOD, 2001, 98 (06) :1935-1941
[43]   Structure and function of a new STAT-induced STAT inhibitor [J].
Naka, T ;
Narazaki, M ;
Hirata, M ;
Matsumoto, T ;
Minamoto, S ;
Aono, A ;
Nishimoto, N ;
Kajita, T ;
Taga, T ;
Yoshizaki, K ;
Akira, S ;
Kishimoto, T .
NATURE, 1997, 387 (6636) :924-929
[44]   Role of phosphatases in lymphocyte activation [J].
Neel, BG .
CURRENT OPINION IN IMMUNOLOGY, 1997, 9 (03) :405-420
[45]   MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex [J].
Ng, HH ;
Zhang, Y ;
Hendrich, B ;
Johnson, CA ;
Turner, BM ;
Erdjument-Bromage, H ;
Tempst, P ;
Reinberg, D ;
Bird, A .
NATURE GENETICS, 1999, 23 (01) :58-61
[46]   Genome-wide expression changes induced by HTLV-1 Tax:: evidence for MLK-3 mixed lineage kinase involvement in Tax-mediated NF-κB activation [J].
Ng, PWP ;
Iha, H ;
Iwanaga, Y ;
Bittner, M ;
Chen, YD ;
Jiang, Y ;
Gooden, G ;
Trent, JM ;
Meltzer, P ;
Jeang, KT ;
Zeichner, SL .
ONCOGENE, 2001, 20 (33) :4484-4496
[47]   Reduction of hematopoietic cell-specific tyrosine phosphatase SHP-1 gene expression in natural killer cell lymphoma and various types of lymphomas/leukemias: Combination analysis with cDNA expression array and tissue microarray [J].
Oka, T ;
Yoshino, T ;
Hayashi, K ;
Ohara, N ;
Nakanishi, T ;
Yamaai, Y ;
Hiraki, A ;
Sogawa, CA ;
Kondo, E ;
Teramoto, N ;
Takahashi, K ;
Tsuchiyama, J ;
Akagi, T .
AMERICAN JOURNAL OF PATHOLOGY, 2001, 159 (04) :1495-1505
[48]   Dnmt2 is not required for de novo and maintenance methylation of viral DNA in embryonic stem cells [J].
Okano, M ;
Xie, SP ;
Li, E .
NUCLEIC ACIDS RESEARCH, 1998, 26 (11) :2536-2540
[49]   SENSITIVE AND RAPID ASSAY ON MT-4 CELLS FOR DETECTION OF ANTIVIRAL COMPOUNDS AGAINST THE AIDS VIRUS [J].
PAUWELS, R ;
DECLERCQ, E ;
DESMYTER, J ;
BALZARINI, J ;
GOUBAU, P ;
HERDEWIJN, P ;
VANDERHAEGHE, H ;
VANDEPUTTE, M .
JOURNAL OF VIROLOGICAL METHODS, 1987, 16 (03) :171-185
[50]  
Pise-Masison CA, 2002, CANCER RES, V62, P3562