The distribution of DNA topoisomerase II isoforms in differentiated adult mouse tissues

Juenke, JoEtta M.; Holden, Joseph A.

doi:10.1016/0167-4781(93)90144-3

Cited by 30 publications

(18 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…low white blood count at nadir and anemia [33]. Indeed, TOP2A is expressed predominantly in proliferating compartments such as bone marrow [18, 37]. The effects of DRZ on the stability and expression of TOP2 isoforms in normal tissues deserve detailed investigations.…”

Section: Discussionmentioning

confidence: 99%

Dexrazoxane may prevent doxorubicin-induced DNA damage via depleting both Topoisomerase II isoforms

et al. 2014

View full text Add to dashboard Cite

BackgroundThe bisdioxopiperazine dexrazoxane (DRZ) prevents anthracycline-induced heart failure, but its clinical use is limited by uncertain cardioprotective mechanism and by concerns of interference with cancer response to anthracyclines and of long-term safety.MethodsWe investigated the effects of DRZ on the stability of topoisomerases IIα (TOP2A) and IIβ (TOP2B) and on the DNA damage generated by poisoning these enzymes by the anthracycline doxorubicin (DOX).ResultsDRZ given i.p. transiently depleted in mice the predominant cardiac isoform Top2b. The depletion was also seen in H9C2 cardiomyocytes and it was attenuated by mutating the bisdioxopiperazine binding site of TOP2B. Consistently, the accumulation of DOX-induced DNA double strand breaks (DSB) by wild-type, although not by mutant TOP2B, was reduced by DRZ. In contrast, the DRZ analogue ICRF-161, which is capable of iron chelation but not of TOP2B binding and cardiac protection, did not deplete TOP2B and did not prevent the accumulation of DOX-induced DSB. TOP2A, re-expressed in cultured cardiomyocytes by fresh serum, was depleted by DRZ along with TOP2B. DRZ depleted TOP2A also from fibrosarcoma-derived cells, but not from lung cancer-derived and human embryo-derived cells. DRZ-mediated TOP2A depletion reduced the accumulation of DOX-induced DSB.ConclusionsTaken together, our data support a model of anthracycline-induced heart failure caused by TOP2B-mediated DSB and of its prevention by DRZ via TOP2B degradation rather than via iron chelation. The depletion of TOP2B and TOP2A suggests an explanation for the reported DRZ interference with cancer response to anthracyclines and for DRZ side-effects.

show abstract

Section: Discussionmentioning

confidence: 99%

Dexrazoxane may prevent doxorubicin-induced DNA damage via depleting both Topoisomerase II isoforms

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Topo II ␣ is shown to be higher in testes, spleen, bone marrow and liver. Topo II ␤ is detected in high levels in differentiated tissue like brain (Jurenke and Holden, 1993;Capranico et al, 1992). However, a systematic study to examine the levels of the isoform of Topoisomerase II, ␣ and ␤ in different regions and cell types of brain is lacking.…”

Section: Introductionmentioning

confidence: 99%

Analysis of age dependent changes of Topoisomerase II α and β in rat brain

Kondapi¹,

Mulpuri²,

Mandraju³

et al. 2004

Intl J of Devlp Neuroscience

View full text Add to dashboard Cite

Eukaryotic Topoisomerase II (Topo II) is present in two isoforms alpha and beta. The alpha isoform is predominantly localized in proliferative tissue, while beta isoform is present in all tissues. In the present study we report the activity and protein levels of Topoisomerase II alpha and beta in rat brains of different age groups viz.: E11 (Embryo day 11), E18 (Embryo day 18), post-natal day 1, young (<10 days), adult (<6 months) and old (>2 years). Topoisomerase II beta isoform is found to be the predominant form in brain tissue but Topoisomerase II alpha is found in embryos up to post-natal day 1. The studies to examine the regional distribution of Topoisomerase II beta in brain showed highest activity in cerebellar region and that too only neuronal cell fraction. There was a significant age-dependent decline in this activity. Hence, Topoisomerase II beta may have some unknown function in cerebellum and the low levels of Topoisomerase II beta activity in ageing cerebellum may contribute to the genomic instability in cerebellar region of ageing brain.

show abstract

“…These cell-specific differences in the expression of isoforms of topo II suggest that they play vital and non-redundant roles in cell growth and differentiation (Meyer et al 1997, Grue et al 1998. Previously, using biochemical and immunological methods, we and others have shown that the isoform expressed in rat testis is topo II (Juenke & Holden 1993, Park et al 1995, Galande & Muniyappa 1996. Comparison of the topo II promoters from humans and animal models, including mice, hamsters and rats, has revealed a high degree of phylogenetic conservation.…”

Section: Resultsmentioning

confidence: 99%

“…Topo II is expressed preferentially in actively proliferating tissues, whereas expression of topo II is restricted to quiescent somatic tissues (Juenke & Holden 1993, Park et al 1995, thereby implicating a relationship between growth regulatory signaling pathways and expression of topo II isoforms. These cell-specific differences in the expression of isoforms of topo II suggest that they play vital and non-redundant roles in cell growth and differentiation (Meyer et al 1997, Grue et al 1998.…”

Section: Resultsmentioning

confidence: 99%

Developmental and hormonal regulation of type II DNA topoisomerase in rat testis

Bakshi

Galande

Bali

et al. 2001

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

Type II DNA topoisomerase (topo II) is required for diverse biological functions including DNA replication, maintenance of genome stability, chromosome segregation and chromosome condensation. While the identity of topo II in rodent testis has been established, the regulation of topo II expression during the development of the postnatal testis and gametogenesis is unclear. Here, we report that rat testis topo II is developmentally and hormonally regulated. Topo II mRNA levels peaked prior to the onset of puberty, declined sharply thereafter and stabilized in adult testis. In contrast, the topo II enzyme content was lower in prepubertal testis but increased after the onset of puberty. Topo II was expressed in a cell-specific manner within germ cells, being detected only in pachytene spermatocytes. While testosterone markedly increased topo II mRNA levels in prepubertal testis, continued treatment failed to enhance topo II mRNA above postpubertal control levels. The extent of topo II activity remained steady regardless of the testosterone-induced increase in topo II mRNA levels. Inhibition of testosterone function in postpubertal animals by ethanedimethane sulphonate (EDS) and flutamide resulted in a significant decrease in topo II gene expression and topo II activity. The administration of exogenous testosterone (T) to EDS-and flutamide-treated rats restored topo II mRNA levels and topo II activity similar to the levels seen in the testis of age-matched control animals. Histochemical analyses of testes indicated that the effect of T on spermatogenesis was separable from its effect on topo II expression. Our results reveal that testosterone acts as a positive regulator of topo II gene expression and is required for the maintenance of topo II expression during the development of the postnatal testis and spermatogenesis.

show abstract

The distribution of DNA topoisomerase II isoforms in differentiated adult mouse tissues

Cited by 30 publications

References 14 publications

Dexrazoxane may prevent doxorubicin-induced DNA damage via depleting both Topoisomerase II isoforms

Dexrazoxane may prevent doxorubicin-induced DNA damage via depleting both Topoisomerase II isoforms

Analysis of age dependent changes of Topoisomerase II α and β in rat brain

Developmental and hormonal regulation of type II DNA topoisomerase in rat testis

Contact Info

Product

Resources

About