Immediate effects of reversible HTLV-ITax function: T-cell activation and apoptosis

Chlichlia, Katerina; Moldenhauer, Gerhard; Daniel, Peter T.; Busslinger, Meinrad; Gazzolo, Louis; Schirrmacher, Volker; Khazaie, Khashayarsha

doi:10.1007/bf02559873

Cited by 56 publications

(88 citation statements)

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“…It can be interpreted as further evidence for the common pathways used by viruses to subvert cell cycle and cell death regulation. Our cell cycle data indeed suggest that an early e ect of HBx expression, during infection by a non-lytic virus such as HBV, is to`activate' quiescent hepatocytes and maintain them in this state in G1 of the cell cycle as reported for the Tax protein of HTLV-1 (Chlichia et al, 1995). It has been shown that HBV replication depends on cell cycle and di erentiation status and is decreased in S phase (Ozer et al, 1996).…”

Section: Discussionsupporting

confidence: 74%

“…The concept that a putative oncogene can modulate both the cell cycle and apoptosis has now been well established for several viral proteins, such as the E1A protein of adenovirus 5 (for a review, see Mymryk, 1996), E2 protein of papillomaviruses (Desaintes et al, 1997;Goodwin et al, 1998), and the Tax protein of HTLV-1 (Chlichia et al, 1995). It can be interpreted as further evidence for the common pathways used by viruses to subvert cell cycle and cell death regulation.…”

Section: Discussionmentioning

confidence: 99%

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Hepatitis B virus X mutants, present in hepatocellular carcinoma tissue abrogate both the antiproliferative and transactivation effects of HBx

et al. 1999

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Chronic infection by HBV is the leading cause of hepatocellular carcinoma in man. Several lines of evidence suggest that the viral transactivator HBx plays a critical role in the molecular pathogenesis of HBVrelated HCC. To study the actual impact of HBx and the mechanism of its action, we have recently cloned and characterized a set of X-sequences from HCC in patients with chronic infection by HBV. In the present study, we have compared the e ects of HBx and its naturally arising mutants on cell growth and viability. We report that HBx inhibits clonal outgrowth of cells and induces apoptosis by a p53-independent pathway. Furthermore, HBx expression induced a late G1 cell cycle block prior to their counterselection by apoptosis. Importantly, mutations in the HBx-gene evolving in hepatocellular carcinoma abolished both HBx-induced growth arrest and apoptosis. Using a panel of engineered mutants we have mapped the growth suppressive e ect of HBx to domains shown to be required for its transactivating function. Based on these results, we propose that abrogation of the anti-proliferative and apoptotic e ects of HBx by naturally occurring mutations might render the hepatocytes susceptible to uncontrolled growth and contribute to multistep hepatocarcinogenesis associated with HBV-infection.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Hepatitis B virus X mutants, present in hepatocellular carcinoma tissue abrogate both the antiproliferative and transactivation effects of HBx

et al. 1999

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“…Recent studies have supported a role for Tax and/or HTLV-1 infection in the induction of apoptosis. Using a hormone inducible Tax expression system, Tax expressing cells were found to be sensitive to Fas ligand mediated cell death (Chen et al, 1997;Chlichlia et al, 1995), and ICE-proteases were shown to be involved in this Tax-mediated apoptosis (Chlichlia et al, 1997). It has also been shown that Rat-1 cells transformed by Tax undergo apoptotic cell death after serum deprivation and constitutive Bcl-2 expression blocks this Tax-mediated apoptosis (Yamada et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…There have been con¯icting reports about the e ect of Tax on apoptosis. Tax has been shown to induce apoptosis in a variety of systems (Chen et al, 1997;Chlichlia et al, 1995Chlichlia et al, ,1997Fujita and Shiku, 1995;Hall et al, 1998;Kitajima et al, 1996;Yamada et al, 1994), consistent with its ability to reduce DNA repair. However, in other reports Tax has been shown to inhibit apoptosis (Brauweiler et al, 1997;Copeland et al, 1994;Tsukahara et al, 1999;Mulloy et al, 1998), supporting its role as a transforming protein and inducer of T cell proliferation.…”

Section: Introductionmentioning

confidence: 86%

HTLV-1 Tax protein sensitizes cells to apoptotic cell death induced by DNA damaging agents

2000

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Transient HTLV-1 Tax expression suppresses cellular nucleotide excision repair, and this e ect correlates with Tax transactivation of the proliferating cell nuclear antigen promoter. The inability to repair DNA damage typically induces apoptotic cell death. Therefore, we investigated the e ect of Tax-mediated suppression of DNA repair on apoptosis in stable Tax-expressing cells. Constitutive Tax expression reduced cellular nucleotide excision repair activity compared with parental and control cells. Tax-expressing cells were also more sensitive to apoptosis induced by DNA damaging agents than control cells. Even though Tax-expressing cells displayed reduced DNA repair, they showed increased DNA replication following UV damage. These results suggest that Tax suppresses the cell's ability to repair DNA damage and stimulates DNA replication even in the presence of damage. The inability to repair DNA damage is likely to stimulate apoptotic cell death in the majority of Tax-expressing cells while the ability to promote DNA replication may also allow the survival of a small population of cells. We propose that together these e ects contribute to the monoclonal nature and low e ciency of HTLV-1 transformation.

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“…In fact, conflicting results have shown that the viral protein Tax, in addition to exerting expected anti-apoptotic effects, also enables HTLV-1-infected cells to undergo apoptosis, under certain experimental conditions. For example, the expression of Tax in an inducible system promoted rather than inhibited cell death [Chlichlia et al, 1995]. This Tax-triggered death was critically dependent on ICEprotease function [Chlichlia et al, 1997] and associated with a marked up-regulation of the Fas ligand (FasL) gene [Chen et al, 1997].…”

Section: Introductionmentioning

confidence: 99%

Modulation of apoptosis during HTLV‐1‐mediated immortalization process in vitro

Matteucci

Balestrieri

Macchi

et al. 2004

Journal of Medical Virology

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Suppression of apoptosis has been proposed as a mechanism involved in the transforming action of human T-cell leukemia/lymphotropic virus type-1 (HTLV-1). However, there is evidence that HTLV-1 and its protein Tax also induce apoptosis. To resolve this apparent paradox, apoptosis was monitored in primary cultures of peripheral blood lymphocytes (PBLs) from healthy donors, following HTLV-1 infection in vitro. High levels of apoptosis in HTLV-1 infected cultures during the first weeks after infection were detected. Apoptosis was not related to the presence of uninfected cells, as revealed by a fluorescence in situ hybridization assay. Successively, a progressive decrease in apoptosis in infected cultures going towards immortalization, was observed. When IL-2 in the medium was replaced by IL-4, allowing the cells to be efficiently infected by HTLV-1 but not immortalized, apoptosis levels tended to increase, instead of decreasing, with the ongoing time. The caspase cascade was remarkably activated in PBLs recently infected in vitro by HTLV-1, but apoptosis was only partly reduced by caspase inhibitors. Even if spontaneous apoptosis was relatively low in long-term cultures of PBLs immortalized by HTLV-1 in vitro, Fas death-receptor expression and function were well conserved. These observations provide a new rationale for explaining the dual effect of HTLV-1 in controlling apoptosis.

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Immediate effects of reversible HTLV-ITax function: T-cell activation and apoptosis

Cited by 56 publications

References 0 publications

Hepatitis B virus X mutants, present in hepatocellular carcinoma tissue abrogate both the antiproliferative and transactivation effects of HBx

Hepatitis B virus X mutants, present in hepatocellular carcinoma tissue abrogate both the antiproliferative and transactivation effects of HBx

HTLV-1 Tax protein sensitizes cells to apoptotic cell death induced by DNA damaging agents

Modulation of apoptosis during HTLV‐1‐mediated immortalization process in vitro

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