Glucose-regulated stresses cause degradation of DNA topoisomerase II? by inducing nuclear proteasome during G1 cell cycle arrest in cancer cells

Kim, Hong-Duck; Tomida, Akihiro; Ogiso, Yasunari; Tsuruo, Takashi

doi:10.1002/(sici)1097-4652(199907)180:1<97::aid-jcp11>3.0.co;2-y

Cited by 23 publications

(16 citation statements)

References 37 publications

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“…Our present findings would be useful in elucidating the mechanisms of topo II␣ degradation in these situations. It should then be noted that topo II␣ often escapes the quiescence-and cell cycle-dependent regulation in tumor cells (15,41,42), suggesting that deregulated proteolysis of topo II␣ may be involved in tumor development by analogy with p27…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, topo II␣ degradation under glucose starvation has been observed in a variety of solid tumor lines, even in cells where the cell cycle-dependent regulation is abrogated (15,18). Thus, the GRDD-and MPN-dependent degradation of topo II␣ might be particularly important for cellular adaptation to severe stress conditions.…”

Section: Discussionmentioning

confidence: 99%

“…Malignant cells within solid tumors are often surrounded by conditions such as glucose deprivation, hypoxia, low pH, and other forms of nutrient deprivation (8,9,14). These physiological conditions in culture can down-regulate the expression of topo II␣ with growth arrest or delay at the G 1 phase of the cell cycle (15). What we found to be consistent with the decreased topo II␣ levels was tumor cells becoming resistant to topo II-directed drugs when stressed by glucose starvation and related culture conditions (16,17).…”

Section: Dna Topoisomerase II (Topo Ii)mentioning

confidence: 99%

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Interaction between Glucose-regulated Destruction Domain of DNA Topoisomerase IIα and MPN Domain of Jab1/CSN5

Yun

Tomida

Andoh

et al. 2004

Journal of Biological Chemistry

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DNA topoisomerase (topo) II␣, an essential enzyme for cell proliferation, is targeted to a proteasome-dependent degradation pathway when human tumor cells are glucose-starved. Here we show that the topo II␣ destabilization depends on the newly identified domain, GRDD (glucose-regulated destruction domain), which was mapped to the N-terminal 70 -170 amino acid sequence. Indeed, the deletion of GRDD conferred a stable feature on topo II␣, whereas the fusion of GRDD rendered green fluorescent protein unstable under glucose starvation conditions. Nuclear localization was a prerequisite for GRDD function, because the inhibition of nuclear translocation resulted in the suppression of GRDD-mediated topo II␣ degradation. Further, GRDD was identified as an interactive domain for Jab1/CSN5, which promoted the degradation of topo II␣ in a manner dependent on the MPN (Mpr1p/ Prd1p N terminus) domain. Depleting Jab1/CSN5 by antisense oligonucleotide and treating cells with the CSNassociated kinase inhibitor, curcumin, inhibited topo II␣ degradation induced by glucose starvation. These findings demonstrate that GRDD can act as a stress-activated degron for regulating topo II␣ stability, possibly through interaction with the MPN domain of Jab1/CSN5. DNA topoisomerase II (topo II)1 is an essential enzyme for eukaryotic cell proliferation and plays important roles in many aspects of the DNA process through modulating the topological states (1). In humans, topo II exists in two closely related isoforms, ␣ and ␤, which share a high degree of structural homology with a ϳ70% sequence identity (2, 3). Three discrete functional domains are embedded in the topo II enzymes (1, 4). The N-terminal and the central domains are responsible for ATPase and catalytic activities, respectively, and the C-terminal domain, the least conserved region, contains the nuclear localization signals (NLSs). Although the structural and the biochemical features are closely related, the topo II isoforms show a great difference in their expression characteristics (4).The expression of topo II␣ is regulated by the state of cellular proliferation, high in proliferation and low in quiescence with a higher cell density or a lower serum concentration. The levels of topo II␣ also change within a single cell cycle, peaking in the G 2 /M phase and declining to a minimal level after M phase completion. However, the levels of topo II␤ are relatively constant throughout the cell cycle and in quiescent and proliferating states (5).The topo II isoforms have been shown to be the molecular target for such clinically important antitumor drugs such as etoposide and doxorubicin (6, 7). The topo II-directed drugs convert this enzyme into a cellular poison by stabilizing the covalent DNA-enzyme intermediates, the so-called cleavable complex. Interestingly, the increase in topo II-cleavable complexes also has been observed in the presence of a number of physiological stressors such as acidic pH, oxidation, and thiol (8, 9). DNA damage resulting from the cleavable complexes is thou...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Dna Topoisomerase II (Topo Ii)mentioning

confidence: 99%

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Interaction between Glucose-regulated Destruction Domain of DNA Topoisomerase IIα and MPN Domain of Jab1/CSN5

Yun

Tomida

Andoh

et al. 2004

Journal of Biological Chemistry

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“…For the synchronized culture, we trapped cells in M phase of the cell cycle by treating them with 40 ng of nocodazole/ml (Wako Pure Chemical Industries, Osaka, Japan) for 9 h, collected cells by gentle pipetting, and reseeded them in fresh culture medium (28,29). Populations of G1-and S-phase cells constituted the majority (typically 60 -70%) of the total cell population at 3 h and 9 h after the release, respectively (28,29).…”

Section: Introductionmentioning

confidence: 99%

Cullin 3 Promotes Proteasomal Degradation of the Topoisomerase I-DNA Covalent Complex

et al. 2004

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DNA topoisomerase I (TOP1)-DNA covalent complexes are the initial lesions produced by antitumor camptothecins (CPTs). The TOP1-directed drugs stimulate degradation of TOP1 via the ubiquitin-proteasome pathway. We found that proteasome inhibition prevents degradation of DNAbound TOP1 and sustains high levels of covalent complexes, thus enhancing CPT-induced cell death. Consistent with this, increased degradation of TOP1-DNA covalent complexes was seen in acquired CPT-resistant cells. We found that the resistant cells showed elevated expressions of Cul3, a member of the cullin family of E3 ubiquitin ligases. The reduction in Cul3 expression by small interfering RNA decreased degradation of TOP1-DNA covalent complexes. Conversely, Cul3 overexpression by stable transfection promoted covalent complex degradation and reduced CPTinduced cell death without affecting basal TOP1 expression levels. These results indicate that Cul3, by promoting proteasomal degradation of TOP1-DNA covalent complexes, becomes an important regulator for cellular CPT sensitivity.

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“…This suggests that 2DG and EF provoke ER stress by utilizing parallel pathways. Kim et al (1999) have reported that, in an attempt to maintain ER homeostasis, cells undergoing glycolytic stress elevate their level of nuclear proteasomal activities raising the possibility that EF synergize with 2DG in increasing ER stress by inhibiting 2DG-induced proteasomal function. This may also explain why combination treatment is more effective in MDA-MB-231 cells than in MCF-7 cells, since the former are more sensitive to proteasomal inhibition.…”

Section: Discussionmentioning

confidence: 99%

Antitumor activity of efrapeptins, alone or in combination with 2-deoxyglucose, in breast cancer in vitro and in vivo

Papathanassiu

MacDonald

Emlet

et al. 2011

Cell Stress and Chaperones

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Efrapeptins (EF), a family of fungal peptides, inhibit proteasomal enzymatic activities and the in vitro and in vivo growth of HT-29 cells. They are also known inhibitors of F 1 F 0 -ATPase, a mitochondrial enzyme that functions as an Hsp90 co-chaperone. We have previously shown that treatment of cancer cells with EF results in disruption of the Hsp90:F 1 F 0 -ATPase complex and inhibition of Hsp90 chaperone activity. The present study examines the effect of EF on breast cancer growth in vitro and in vivo. As a monotherapy, EF inhibited cell proliferation in vitro with an IC 50 value ranging from 6 nM to 3.4 μM. Inhibition of Hsp90 chaperone function appeared to be the dominant mechanism of action and the factor determining cellular sensitivity to EF. In vitro inhibition of proteasome became prominent in the absence of adequate levels of Hsp90 and F 1 F 0 -ATPase as in the case of the relatively EF-resistant MDA-MB-231 cell line. In vivo, EF inhibited MCF-7 and MDA-MB-231 xenograft growth with a maximal inhibition of 60% after administration of 0.15 and 0.3 mg/kg EF, respectively. 2-Deoxyglucose (2DG), a known inhibitor of glycolysis, acted synergistically with EF in vitro and antagonistically in vivo. In vitro, the synergistic effect was attributed to a prolonged endoplasmic reticulum (ER) stress. In vivo, the antagonistic effect was ascribed to the downregulation of tumoral and/or stromal F 1 F 0 -ATPase by 2DG.

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Glucose-regulated stresses cause degradation of DNA topoisomerase II? by inducing nuclear proteasome during G1 cell cycle arrest in cancer cells

Cited by 23 publications

References 37 publications

Interaction between Glucose-regulated Destruction Domain of DNA Topoisomerase IIα and MPN Domain of Jab1/CSN5

Interaction between Glucose-regulated Destruction Domain of DNA Topoisomerase IIα and MPN Domain of Jab1/CSN5

Cullin 3 Promotes Proteasomal Degradation of the Topoisomerase I-DNA Covalent Complex

Antitumor activity of efrapeptins, alone or in combination with 2-deoxyglucose, in breast cancer in vitro and in vivo

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