Role of proteasomal degradation in the cell cycle-dependent regulation of DNA topoisomerase IIα expression☆

Salmena, Leonardo; Lam, Viengthong; McPherson, J. Peter; Goldenberg, Gerald J.

doi:10.1016/s0006-2952(01)00580-9

Cited by 30 publications

(17 citation statements)

References 23 publications

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“…Indeed, topo II␣ also is degraded by proteasome during adenovirus E1A-induced apoptosis (20,26). Proteasome-mediated degradation also appears to be involved in cell cycle-dependent expression of this enzyme, especially in the transition from M to G 1 cell cycle phase (40). Although not determined so far, the proteasome might be involved in decreased expression of topo II␣ in the quiescent cell state.…”

Section: Discussionmentioning

confidence: 96%

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: 96%

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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“…Topo IIα expression is known to be regulated by proteasomal degradation, with a reported half life of approximately 6 hours in the MCF7 breast cancer cell line (13). To determine the kinetics of topo IIα expression and activity in our system, 8226/S and 8226/Dox1V cells were treated with 2.5 nM bortezomib for 6, 14, or 24 hours.…”

Section: Bortezomib Treatment Increases Topo Iiα Expression and Activitymentioning

confidence: 99%

“…Previous studies have shown that the cell cycle-dependent expression of topo IIα is regulated by proteasomal degradation (13). The 26S proteasome is a multicatalytic enzyme complex that is the primary component of the protein degradation pathway of the cell (14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

Proteasomal inhibition stabilizes topoisomerase IIα protein and reverses resistance to the topoisomerase II poison ethonafide (AMP-53, 6-ethoxyazonafide)

Congdon

Pourpak

Escalante

et al. 2008

Biochemical Pharmacology

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Multiple myeloma (MM) is an incurable malignancy of plasma cells. Although multiple myeloma patients often respond to initial therapy, the majority of patients will relapse with disease that is refractory to further drug treatment. Thus, new therapeutic strategies are needed. One common mechanism of acquired drug resistance involves a reduction in the expression or function of the drug target. We hypothesized that the cytotoxic activity of topoisomerase II (topo II) poisons could be enhanced, and drug resistance overcome, by increasing the expression and activity of the drug target, topo II in myeloma cells. To test this hypothesis, we evaluated the cytotoxicity of the anthracenecontaining topo II poison, ethonafide (AMP-53/6-ethoxyazonafide), in combination with the proteasome inhibitor bortezomib (PS-341/Velcade). Combination drug activity studies were done in 8226/S myeloma cells and its drug resistant subclone, 8226/Dox1V. We found that a 24-hour treatment of cells with bortezomib maximally increased topo IIα protein expression and activity, and consistently increased the cytotoxicity of ethonafide in the 8226/S and 8226/Dox1V cell lines. This increase in cytotoxicity corresponded to an increase in DNA double-strand breaks, as measured by the neutral comet assay. Therefore, increasing topo IIα expression through inhibition of proteasomal degradation increased DNA double-strand breaks and enhanced the cytotoxicity of the topo II poison ethonafide. These data suggest that bortezomib-mediated stabilization of topo IIα expression may potentiate the cytotoxic activity of topo II poisons and thereby, provide a strategy to circumvent drug resistance.

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“…BiP overexpressing cells do not show a survival disadvantage when exposed to agents that lead to ER stress (Morris et al, 1997), indicating that topoisomerase II␣ probably does not negatively affect cell survival under these stress conditions. Unfortunately, it has not been possible to ectopically express topoisomerase II␣ in mammalian cells (Salmena et al, 2001) to determine whether enforced expression of this enzyme diminishes survival under UPR-inducing conditions. It has also been suggested that elevated expression of the ER chaperone BiP plays a direct role in resistance to topoisomerase II-targeting agents (Rao et al, 2002;Gosky and Chatterjee, 2003;Reddy et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Activation of the Unfolded Protein Response Is Necessary and Sufficient for Reducing Topoisomerase IIα Protein Levels and Decreasing Sensitivity to Topoisomerase-Targeted Drugs

Gray

Mann

Nitiss³

et al. 2005

Mol Pharmacol

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A wide range of chemotherapeutic agents has been identified that are active against solid tumors. However, resistance remains an important obstacle to the development of curative regimens. Whereas much attention has been paid to acquired drug resistance, a variety of physiological pathways also have been described that reduce the sensitivity of previously untreated tumors to cytotoxic antitumor agents. Treatment of cells with pharmacological agents that alter the environment of the endoplasmic reticulum (ER) and activate the unfolded protein response (UPR) can render cells resistant to topoisomerase II poisons. We describe experiments showing that activation of the mammalian ER stress response is both necessary and sufficient to decrease topoisomerase II␣ protein levels and to render cells resistant to etoposide, a topoisomerase II-targeting drug. This is not caused by the elevated levels of BiP that are a hallmark of this response, because a cell line that has been engineered to overexpress BiP does not show increased resistance to etoposide. The UPR was shown to be required for altered drug sensitivity, because the BiP-overexpressing cell line, which is unable to activate the UPR, did not show decreased topoisomerase II levels or increased resistance to etoposide in response to stress conditions. The transient overexpression of an unfolded protein activated the UPR and led to the concomitant loss of topoisomerase II␣ protein from the cells, demonstrating that UPR activation is sufficient for the changes in topoisomerase II levels that had been observed previously with pharmacological induction of the UPR.

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Role of proteasomal degradation in the cell cycle-dependent regulation of DNA topoisomerase IIα expression☆

Cited by 30 publications

References 23 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

Proteasomal inhibition stabilizes topoisomerase IIα protein and reverses resistance to the topoisomerase II poison ethonafide (AMP-53, 6-ethoxyazonafide)

Activation of the Unfolded Protein Response Is Necessary and Sufficient for Reducing Topoisomerase IIα Protein Levels and Decreasing Sensitivity to Topoisomerase-Targeted Drugs

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