Effect of polyamine depletion on chromatin structure in U-87 MG human brain tumour cells

Basu, Hirak S.; Sturkenboom, Mcjm; Delcros, Jean‐Guy; Csokan, P. P.; Szöllősi, János; Feuerstein, Burt G.; Marton, L. J.

doi:10.1042/bj2820723

Cited by 36 publications

(19 citation statements)

References 36 publications

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“…However, the increased expression of SSAT is only observed in the presence of analogue or natural polyamines, suggesting that the activity of Nrf-2 is altered in the presence of the cation. Basu et al (41,42) have demonstrated profound changes in DNA conformation in the presence of the polyamine analogues. It has also been shown that DNA/protein interactions can be altered by the natural polyamines, as demonstrated by examining the effects of polyamines on restriction FIG.…”

Section: Discussionmentioning

confidence: 99%

The Identification of a Cis-element and a Trans-acting Factor Involved in the Response to Polyamines and Polyamine Analogues in the Regulation of the Human Spermidine/Spermine N 1-Acetyltransferase Gene Transcription

Wang¹,

Xiao²,

Thiagalingam³

et al. 1998

Journal of Biological Chemistry

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The superinduction of spermidine/spermine N 1 -acetyltransferase (SSAT) gene has been associated with a cytotoxic response to a new class of antineoplastic polyamine analogues. The initial mechanism of SSAT superinduction is an increase in transcription in response to analogue exposure. This increased transcription appears to be modulated through the association between a nuclear protein factor and a cis-element described here as the polyamine-responsive element (PRE). The PRE was identified as a 9-base pair sequence, 5-TATGACTAA-3, in the context of a 31-base pair stretch from -1522 to -1492 base pairs with respect to the SSAT transcriptional start site. This element binds a nuclear factor from polyamine analogue-responsive cells, but not from polyamine analogue-insensitive cells. The labeled PRE was used to clone and identify the transcription factor, Nrf-2, that binds constitutively to the PRE sequence. Although the PRE sequence shares homology to the originally identified Nrf-2 recognition sequence, the two sequences are not identical. The Nrf-2 transcription factor appears only to be present in cell types that are capable of expressing high amounts of SSAT. The results of these studies suggest that Nrf-2, bound to the PRE, plays an important regulatory role of expression of the human SSAT gene.The requirement for polyamines in growth and development is absolute in eukaryotic cells (1). Although this requirement has been well established, some of the precise molecular functions of the polyamines have only recently been elucidated. Several newly synthesized polyamine analogues have been examined for their potential as antitumor agents (2-4). These compounds have been designed to alter the regulation of polyamine metabolism and interfere with the normal functions of polyamines in tumor cells. Some of these compounds appear to act in an association with an ability to superinduce the expression of spermidine/spermine N 1 -acetyltransferase (SSAT), 1 the rate-limiting enzyme in polyamine catabolism (5-7). The superinduction of SSAT has been associated with a phenotypespecific sensitivity to some of the antitumor polyamine analogues, and there are several reports demonstrating superinduction of SSAT and tumor cell toxicity (8 -13). Therefore, there is considerable interest in elucidating the mechanisms that differentiate sensitive tumors from analogue-insensitive tumors and normal tissue.Control of the analogue-mediated superinduction of SSAT is initiated at the level of transcription (14, 15). The -fold induction of SSAT transcription by analogue exposure is relatively small (2-7-fold) compared with the ultimate induction of enzyme activity; however, this increased transcription is necessary for the downstream events, which can result in Ͼ1000-fold increases in SSAT activity (8,16,17). Here we identify a cis-element in the 5Ј regulatory region of the human SSAT and define it as a polyamine-responsive element (PRE). Further, electrophoretic mobility shift assay (EMSA) results demonstrate that the PRE is bound by a...

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Section: Discussionmentioning

confidence: 99%

The Identification of a Cis-element and a Trans-acting Factor Involved in the Response to Polyamines and Polyamine Analogues in the Regulation of the Human Spermidine/Spermine N 1-Acetyltransferase Gene Transcription

Wang¹,

Xiao²,

Thiagalingam³

et al. 1998

Journal of Biological Chemistry

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“…DNA topoisomerase II levels were unchanged after treatment with MAP/AbeAdo. The third explanation seems the most likely, considering that changes in polyamine levels may modify the activity of other DNA-processing enzymes (Basu et al, 1992) and are believed to affect the DNA binding of transcription factors (Celano et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

Treatment with inhibitors of polyamine biosynthesis, which selectively lower intracellular spermine, does not affect the activity of alkylating agents but antagonizes the cytotoxicity of DNA topoisomerase II inhibitors

Desiderio

Bergamaschi²,

Mascellani³

et al. 1997

Br J Cancer

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Summary Inhibitors of ornithine decarboxylase (ODC), such as a-difluoromethylornithine (DFMO), may influence the cytotoxicity of anti-tumour agents that interact with DNA. Intracellular levels of putrescine and spermidine were markedly reduced by ODC inhibitors while the level of spermine, which is the main polyamine in nuclei, was unchanged. By combining a novel inhibitor of ODC, such as (2R, 5R)-6-heptyne-2,5-diamine (MDL 72.175, MAP), with an inhibitor of S-adenosylmethionine decarboxylase (SAMDC), such as 5'-{[(Z)-4-aminobut-2-enyl]methylamino}-5'-deoxyadenosine (MDL 73.81 1, AbeAdo), spermine was selectively depleted in a human ovarian cancer cell line OVCAR-3 (i.e. spermine became almost undetectable whereas the levels of spermidine and putrescine were not affected). The . The addition of spermine before drug treatment restored the sensitivity to the DNA topoisomerase 11 inhibitors, thus indicating that the reduced effect was related to the intracellular spermine level. The reason for the reduction in cytotoxicity is unclear, but it does not appear to be related to a cell cycle effect or to a decrease in the intracellular level of DNA topoisomerase 11. Drugs that modify polyamine biosynthesis are under early clinical development as potential new anti-tumour agents. These findings illustrate the need for caution in combining such drugs with DNA topoisomerase 11 inhibitors.

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“…Polyamine depletion has been shown to alter the state and structure of chromatin (Snyder, 1989;Basu et al, 1992) and this may affect the DNA replication apparatus. Polyamines have also been shown to directly stimulate the activity of DNA polymerases (Hironaka et al, 1987;Bachrach and Abu-Elheiga, 1990).…”

Section: Discussionmentioning

confidence: 99%

Impairment of DNA Replication within One Cell Cycle after Seeding of Cells in the Presence of a Polyamine‐Biosynthesis Inhibitor

Fredlund

Oredsson

1996

European Journal of Biochemistry

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Chinese hamster ovary (CHO) cells in the plateau phase were seeded in the absence or presence of S mM 2-difluoromethylornithine (F,MeOm), an enzyme-activated irreversible inhibitor of ornithine decarboxylase. The thymidine analogue bromodeoxyuridine (BrdUrd, 5 pM) was added to the culture medium 30 min before sampling of the cells, which occurred 1-17 h after seeding. Using flow cytometry, coupled with an indirect immunofluorescence technique, which utilized monoclonal BrdUrd and secondary fluorescein-isothiocyanate-conjugated antibodies, and the DNA stain propidium iodide, cellular BrdUrd and DNA contents were quantified. To determine if there was a perturbation in the progression of cells through the S phase, the distribution of BrdUrd-labelled cells in the S phase was evaluated in two ways: (a) by calculating the mean DNA content of BrdUrd-labelled cells in relation to the mean DNA contents of G, and G, cells (relative movement,,,,) and (b) by studying DNA histograms of BrdUrdlabelled cells. By using both evaluation methods, we show that DNA replication was impaired during the first cell cycle that was initiated after seeding CHO cells in the presence of F,MeOrn. The cells appeared to enter the S phase normally but were then delayed in their progression through this phase. The impairment of F,MeOm treatment on DNA replication was apparent at 9 h after seeding, a time point at which the putrescine pool was depleted, the spermidine pool was approximately halved, and the spermine pool was unaffected, when compared to corresponding pools of control cells. When cells were seeded in the presence of F,MeOm and putrescine, the effect on DNA replication was prevented. The rates of incorporation of ['Hluridine and ['H]leucine into RNA and protein, respectively, were the same in control and in F,MeOrn-treated cells for at least up to 11 h after seeding.

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Effect of polyamine depletion on chromatin structure in U-87 MG human brain tumour cells

Cited by 36 publications

References 36 publications

The Identification of a Cis-element and a Trans-acting Factor Involved in the Response to Polyamines and Polyamine Analogues in the Regulation of the Human Spermidine/Spermine N 1-Acetyltransferase Gene Transcription

The Identification of a Cis-element and a Trans-acting Factor Involved in the Response to Polyamines and Polyamine Analogues in the Regulation of the Human Spermidine/Spermine N 1-Acetyltransferase Gene Transcription

Treatment with inhibitors of polyamine biosynthesis, which selectively lower intracellular spermine, does not affect the activity of alkylating agents but antagonizes the cytotoxicity of DNA topoisomerase II inhibitors

Impairment of DNA Replication within One Cell Cycle after Seeding of Cells in the Presence of a Polyamine‐Biosynthesis Inhibitor

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