Cytogenetic studies on the adult T-cell leukemia in Japan

Fujita, Kazuyuki; Yamasaki, Yoshihiro; Sawada, Hitoshi; Izumi, Yoichiro; Fukuhara, Shirou; Uchino, Haruto

doi:10.1016/0145-2126(89)90120-3

Cited by 21 publications

(15 citation statements)

References 30 publications

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“…This is an important feature of Tax's e ect on DNA repair because, if Tax suppression of DNA repair leads to an accumulation of DNA mutations, as our model predicts, it will likely require long term Tax expression to see this e ect. This ®nding is consistent with other reports suggesting that Tax expression promotes an accumulation of DNA damage (Majone et al, 1993;Saggioro et al, 1994;Miyake et al, 1999), and that HTLV-1 transformed cells exhibit various chromosomal abnormalities (Fujita et al, 1989;Kamada et al, 1992). It is not likely that Tax directly induces mutations, but rather that Tax suppresses repair of DNA damage resulting from other sources.…”

Section: Discussionsupporting

confidence: 92%

“…Thus, Tax protein may facilitate malignant progression by decreasing the cell's ability to repair genetic damage in infected cells. Indeed, cytogenetic studies have shown that leukemic cells from ATL patients contain clonal chromosomal abnormalities, most commonly including deletions and translocations (Fujita et al, 1989;Kamada et al, 1992). Although chromosomal changes are common in transformed ATL cells, no consistent abnormalities have been found in all ATL patients (Sandberg, 1991), suggesting that a generalized deregulation of host DNA replication and repair machinery occurs during the development of ATL.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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

2000

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“…A functional p53 signaling pathway could rescue Tax-mediated suppression of DNA repair (34). These reports are consistent with the observations that HTLV-1-transformed cells exhibit chromosomal abnormalities (17,31). The DNA damaging and mutagenic properties of Tax may favor the induction of genetic changes that are required for tumor initiation and progression.…”

Section: Tax-induced Apoptotic Cell Deathsupporting

confidence: 79%

Redox Events in HTLV-1 Tax-Induced Apoptotic T-Cell Death

Chlichlia

Łos

Schulze‐Osthoff

et al. 2002

Antioxidants & Redox Signaling

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“…DNA replication in the presence of unrepaired lesions might increase the accumulation of DNA damage and chromosomal breaks. Indeed, HTLV-1-transformed cells display extensive chromosomal aberrations and Tax expression has been shown to increase gene amplification and mutation frequency (16,26,30,35,36). Early attenuation of the DNA damage response may be a mechanism by which HTLV-1 controls the cell cycle to gain a proliferative advantage in infected cells.…”

Section: Vol 82 2008mentioning

confidence: 99%

Human T-Cell Leukemia Virus Type 1 Tax Attenuates the ATM-Mediated Cellular DNA Damage Response

Chandhasin

Ducu

Berkovich

et al. 2008

J Virol

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Genomic instability, a hallmark of leukemic cells, is associated with malfunctioning cellular responses to DNA damage caused by defective cell cycle checkpoints and/or DNA repair. Adult T-cell leukemia, which can result from infection with human T-cell leukemia virus type 1 (HTLV-1), is associated with extensive genomic instability that has been attributed to the viral oncoprotein Tax. How Tax influences cellular responses to DNA damage to mediate genomic instability, however, remains unclear. Therefore, we investigated the effect of Tax on cellular pathways involved in recognition and repair of DNA double-strand breaks. Premature attenuation of ATM kinase activity and reduced association of MDC1 with repair foci were observed in Tax-expressing cells. Following ionizing radiation-induced S-phase checkpoint activation, Tax-expressing cells progressed more rapidly than non-Tax-expressing cells toward DNA replication. These results demonstrate that Tax expression may allow premature DNA replication in the presence of genomic lesions. Attempts to replicate in the presence of these lesions would result in gradual accumulation of mutations, leading to genome instability and cellular transformation.Preserving genomic integrity is critical for all living systems. The integrity and survival of a cell depend on the stability of its DNA. Damaged DNA is detected by cellular sensing systems, which activate specific DNA repair pathways. Malfunction of this repair network, collectively known as the DNA damage response, leads to DNA mutations, a subset of which can promote cellular transformation. Double-stranded DNA breaks (DSBs) arise from genotoxic insults and normal physiological processes such as DNA replication (24, 38). The mechanisms by which eukaryotic cells sense DNA breaks remain to be elucidated, but one of the earliest detectable events in DNA damage sensing is the activation of the ataxia telangiectasia mutated (ATM) kinase (45).ATM is a member of the PI3K-like kinase family and is mutated in ataxia telangiectasia patients (45). Immediately after exposure of cells to DSB-inducing agents such as ionizing radiation (IR) and radiomimetic drugs, changes in chromatin structure activate the intermolecular autophosphorylation of ATM on Ser1981, resulting in the dissociation of inactive ATM dimers into active monomers that allow substrate accessibility to the ATM kinase domain (2). ATM substrates include cellular targets such as NBS1, Chk2, p53, MDC1, histone 2AX (H2AX), and BRCA1, which are key players in the maintenance of genomic integrity (5,19,44,47). Some of these substrates are phosphorylated by ATM in the nucleoplasm, while others are phosphorylated at sites of DNA damage where ATM is recruited via interaction with the Mre11/Rad50/NBS1 (MRN) complex. At sites of DNA breaks within chromatin, the phosphorylation of H2AX and MDC1 by ATM establishes a positive-feedback loop that maintains ATM autophosphorylation and amplifies the DNA damage response (31). Genetic defects in crucial parts of this network lead to a grou...

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Cytogenetic studies on the adult T-cell leukemia in Japan

Cited by 21 publications

References 30 publications

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

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

Redox Events in HTLV-1 Tax-Induced Apoptotic T-Cell Death

Human T-Cell Leukemia Virus Type 1 Tax Attenuates the ATM-Mediated Cellular DNA Damage Response

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