Dual targeting of transformed and untransformed HTLV-1-infected T cells by DHMEQ, a potent and selective inhibitor of NF- B, as a strategy for chemoprevention and therapy of adult T-cell leukemia

Watanabe, Miki; Ohsugi, Takeo; Shoda, Munehito; Ishida, Takeshi; Aizawa, Shojiro; Maruyama-Nagai, Masae; Utsunomiya, Atae; Koga, Shin; Yamada, Yasuaki; Kamihira, Shimeru; Okayama, Akira; Kojima, Hiroshi; Uozumi, Kimiharu; Yamaguchi, Kazunari; Higashihara, Masaaki; Umezawa, Kazuo; Horie, Ryouichi

doi:10.1182/blood-2004-09-3646

Cited by 115 publications

(109 citation statements)

References 53 publications

(56 reference statements)

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“…Tax1 interacts with transcription factors and activates the cyclic-AMP response element and activating transcription factor (ATF) binding (CREB/ATF) pathway, the NF-kB pathway and the serum response factor (SRF) pathway. Tax activation of CREB/ATF is needed for an efficient viral gene expression, while the permanent activation of NF-kB has been suggested to be critical for evading apoptosis in HTLV-1-infected cells (Watanabe et al, 2005). Consistent with this, a large body of evidence indicates that Tax activates a number of cellular genes involved in the regulation of the cellular proliferation and interferes with the cell cycle control machinery.…”

Section: Characterization Of the Htlv/stlv-3 Tax Proteinmentioning

confidence: 87%

The tax protein from the primate T-cell lymphotropic virus type 3 is expressed in vivo and is functionally related to HTLV-1 Tax rather than HTLV-2 Tax

et al. 2006

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Human T-cell leukemia virus and simian T-cell leukemia virus (STLV) form the primate T-cell lymphotropic viruses group. Human T-cell leukemia virus type 1 and type 2 (HTLV-1 and HTLV-2) encode the Tax viral transactivator (Tax1 and Tax2, respectively). Tax1 possesses an oncogenic potential and is responsible for cell transformation both in vivo and in vitro. We and others have recently discovered the existence of human Tcell lymphotropic virus type 3. However, there is currently no evidence for the presence of a Tax protein in HTLV-3-infected individuals. We show that the serum of an HTLV-3 asymptomatic carrier and the sera of two STLV-3-infected monkeys contain specific anti-Tax3 antibodies. We also show that tax3 mRNA is present in the PBMCs obtained from an STLV-3-infected monkey, demonstrating that Tax3 is expressed in vivo. We further demonstrate that Tax3 intracellular localization is very similar to that of Tax1 and that Tax3 binds to both CBP and p300 coactivators. Using purified Tax3, we show that the protein increases transcription from a 4TxRE G-free cassette plasmid in an in vitro transcription assay. In all cell types tested, including transiently transfected lymphocytes, Tax3 activates its own promoter STLV-3 long terminal repeat (LTR), which contains only two Tax Responsive Elements (TREs), and activates also HTLV-1 and HTLV-2 LTRs. In addition, Tax3 also activates the NF-jB pathway. We also show that Tax3 possesses a PDZ-binding sequence at its C-terminal end. Our results demonstrate that Tax3 is a transactivator, and that its properties are more similar to that of Tax1, rather than of Tax2. This suggests the possible occurrence of lymphoproliferative disorders among HTLV-3-infected populations.

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Section: Characterization Of the Htlv/stlv-3 Tax Proteinmentioning

confidence: 87%

The tax protein from the primate T-cell lymphotropic virus type 3 is expressed in vivo and is functionally related to HTLV-1 Tax rather than HTLV-2 Tax

et al. 2006

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“…[46][47][48] The effect of Bay 11-7082, dehydroxymethylepoxyquinomicin and NIK-333 on growth suppression of HTLV-I-infected T-cell lines occurred at an IC 50 of 2.5-5.0, 13-27 and 9.2-24.2 lM, respectively. On the other hand, IC 50 of hG9NC(null) ranged from 0.012 to 0.095 lM.…”

Section: R E T R a C T Ementioning

confidence: 99%

Retracted: A modified version of galectin‐9 suppresses cell growth and induces apoptosis of human T‐cell leukemia virus type I‐infected T‐cell lines

Okudaira

Hirashima

Ishikawa

et al. 2007

Intl Journal of Cancer

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ATL is a fatal malignancy of T lymphocytes caused by HTLV-I infection and remains incurable. Galectins are a family of animal lectins that function both extracellularly (by interacting with cell surface and extracellular matrix glycoproteins and glycolipids) and intracellularly (by interacting with cytoplasmic and nuclear proteins) to modulate signaling pathways. We found that protease-resistant galectin-9 by modification of its linker peptide, hG9NC(null), prevented cell growth of HTLV-I-infected T-cell lines and primary ATL cells. The suppression of cell growth was inhibited by lactose, but not by sucrose, indicating that b-galactoside binding is essential for hG9NC(null)-induced cell growth suppression. hG9NC(null) induced cell cycle arrest by reducing the expression of cyclin D1, cyclin D2, cyclin B1, Cdk1, Cdk4, Cdk6, Cdc25C and c-Myc, and apoptosis by reducing the expression of XIAP, c-IAP2 and survivin. Most of these genes are regulated by NF-jB, which plays a critical role in oncogenesis by HTLV-I. hG9NC(null) suppressed IjBa phosphorylation, resulting in suppression of NF-jB. Most importantly, treatment with hG9NC(null) (6.7 mg/kg injected intraperitoneally every day) reduced tumor formation from an HTLV-I-infected T-cell line when these cells were inoculated subcutaneously into SCID mice. Our results suggest that hG9NC(null) could be a suitable agent for the management of ATL. ' 2007 Wiley-Liss, Inc.Key words: galectin-9; HTLV-I; ATL; NF-kB; apoptosis ATL is a unique malignancy of mature CD4-positive T cells caused by HTLV-I. 1-3 ATL is subclassified into 4 subtypes: acute, lymphoma, chronic and smoldering. In the relatively indolent smoldering and chronic types, the median survival time is more than 2 years. However, at present, there is no accepted curative therapy for ATL and the condition often progresses to death with a median survival time of 13 months in aggressive ATL. 4 Chemotherapies that are specifically known to be active against other lymphoid malignancies are ineffective for treating aggressive forms of ATL. Death is usually due to severe infection or hypercalcemia. Therefore, the establishment of new therapeutic strategies for ATL is very important.Galectins are a family of soluble b-galactoside binding animal lectins. To date, 14 members of the galectin family have been identified. Each member exhibits diverse biological functions and many of them appear to function in cellular homeostasis through regulation of cell adhesion, cell proliferation, cell death and chemoattraction. [5][6][7][8][9] The members can be classified into 3 subtypes according to their structures. The prototype (galectin-1, -2, -7, -10 and -13) and chimera type (galectin-3) galectins have a single CRD and they usually form a noncovalent homodimer resulting in homobifunctional sugar binding activity. Tandem-repeat type galectins (galectin-4, -8, -9 and -12) have two CRDs, which generally show different sugar binding specificities, joined by a linker peptide. This heterobifunctional property makes them capable of cros...

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“…30,31 Genomic DNA from PBMCs was isolated using a QIAGEN Blood Kit (QIAGEN). Quantitative real-time PCR was performed using multiplex PCR with 2 sets of primers specific for the HTLV-1 provirus and the human gene encoding the RNase P enzyme.…”

Section: Viral Marker Assaysmentioning

confidence: 99%

Human T-cell leukemia virus type I (HTLV-1) proviral load and disease progression in asymptomatic HTLV-1 carriers: a nationwide prospective study in Japan

Iwanaga

Watanabe

Utsunomiya

et al. 2010

Blood

296

247

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Dual targeting of transformed and untransformed HTLV-1-infected T cells by DHMEQ, a potent and selective inhibitor of NF- B, as a strategy for chemoprevention and therapy of adult T-cell leukemia

Cited by 115 publications

References 53 publications

The tax protein from the primate T-cell lymphotropic virus type 3 is expressed in vivo and is functionally related to HTLV-1 Tax rather than HTLV-2 Tax

The tax protein from the primate T-cell lymphotropic virus type 3 is expressed in vivo and is functionally related to HTLV-1 Tax rather than HTLV-2 Tax

Retracted: A modified version of galectin‐9 suppresses cell growth and induces apoptosis of human T‐cell leukemia virus type I‐infected T‐cell lines

Human T-cell leukemia virus type I (HTLV-1) proviral load and disease progression in asymptomatic HTLV-1 carriers: a nationwide prospective study in Japan

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