Downregulation of topoisomerase IIβ in myeloid leukemia cell lines leads to activation of apoptosis following all-trans retinoic acid-induced differentiation/growth arrest

Chikamori, Kenichi; Hill, Jason E.; Grabowski, Dale; Zarkhin, Eli; Grozav, Adrian G.; Vaziri, S. A.; Wang, J; Gudkov, Andrei V.; Rybicki, L. A.; Bukowski, Ronald M.; Yen, Andrew; Tanimoto, Mitsune; Ganapathi, Mahrukh K.; Ganapathi, Ram

doi:10.1038/sj.leu.2404351

Cited by 30 publications

(24 citation statements)

References 25 publications

(42 reference statements)

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“…Stable down regulation (8, Supplementary Figure S2) of either topo IIα (72 ± 7.2%) or topo IIβ (96 ± 4.1%) in HL-60 cells (HL-60/sitopo IIα or HL-60/sitopo IIβ, respectively) led to an increase in the pseudomitotic index compared to control cells (HL-60/siGFP) (Figure 3A), confirming that the decatenation checkpoint is regulated by both topo IIα and topo IIβ and is most efficient when both isoforms are present. Our results demonstrating a higher pseudomitotic index in topo IIβ-deficient cells (HL-60/si-topo IIβ), which express higher levels of topo IIα and lower levels of topo IIβ compared to topo IIα-deficient cells, supports our finding in HTETOP cells that the topo IIβ isoform may be more proficient in regulating the decatenation checkpoint.…”

Section: Resultsmentioning

confidence: 99%

“…These cDNAs were cloned in the pHT212 plasmid and transformed in the Saccharomyces cerevisiae yeast strain, BJ201, for preparing recombinant protein for in vitro decatenation assay as described earlier (22,23). The cDNAs were also cloned in the neo-containing IRES-enhanced green fluorescent protein expression pEIE vector described earlier (8) for expressing the recombinant proteins in the genetically engineered fibrosarcoma cell line, HTETOP (25) and in the m -AMSA-resistant HL-60 cell line (HL-60/AMSA-R), which does not express the topo IIβ protein (8,26). …”

Section: Methodsmentioning

confidence: 99%

“…Construction of HL-60 cells (ATCC, Manassas, VA, USA) stably transfected with topo IIα or topo IIβ sh-RNA (HL-60/si-topo IIα or HL-60/si-topo IIβ, respectively) as well as the HL-60/AMSA-R stably transfected with WT topo IIβ cDNA (HL-60/AMSA-R/topo IIβ) was previously described (8). Cultures of these HL-60 cells were maintained in RPMI-1640 supplemented with 10% fetal bovine serum and 2 mM l -glutamine at 37°C in a humidified atmosphere of 5% CO 2 and 95% air.…”

Section: Methodsmentioning

confidence: 99%

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Roles of the C-terminal domains of topoisomerase IIα and topoisomerase IIβ in regulation of the decatenation checkpoint

Kozuki

Chikamori

Surleac

et al. 2017

Nucleic Acids Research

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Topoisomerase (topo) IIα and IIβ maintain genome stability and are targets for anti-tumor drugs. In this study, we demonstrate that the decatenation checkpoint is regulated, not only by topo IIα, as previously reported, but also by topo IIβ. The decatenation checkpoint is most efficient when both isoforms are present. Regulation of this checkpoint and sensitivity to topo II-targeted drugs is influenced by the C-terminal domain (CTD) of the topo II isoforms and by a conserved non-catalytic tyrosine, Y640 in topo IIα and Y656 in topo IIβ. Deletion of most of the CTD of topo IIα, while preserving the nuclear localization signal (NLS), enhances the decatenation checkpoint and sensitivity to topo II-targeted drugs. In contrast, deletion of most of the CTD of topo IIβ, while preserving the NLS, and mutation of Y640 in topo IIα and Y656 in topo IIβ inhibits these activities. Structural studies suggest that the differential impact of the CTD on topo IIα and topo IIβ function may be due to differences in CTD charge distribution and differential alignment of the CTD with reference to transport DNA. Together these results suggest that topo IIα and topo IIβ cooperate to maintain genome stability, which may be distinctly modulated by their CTDs.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Roles of the C-terminal domains of topoisomerase IIα and topoisomerase IIβ in regulation of the decatenation checkpoint

Kozuki

Chikamori

Surleac

et al. 2017

Nucleic Acids Research

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“…43 In addition, Prdx2 has been reported to have an important role in the inhibition of apoptosis in a novel pathway distinct from Bcl-2. 44,45 The increased expression of Prdx2 following treatment with pCons might shed light on the mechanism by which peptide tolerization decreases apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Distinct gene signature revealed in white blood cells, CD4+ and CD8+ T cells in (NZBx NZW) F1 lupus mice after tolerization with anti-DNA Ig peptide

et al. 2010

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Tolerizing mice polygenically predisposed to lupus-like disease (NZB/NZW F1 females) with a peptide mimicking anti-DNA IgG sequences containing MHC class I and class II T cell determinants (pConsensus, pCons) results in protection from full-blown disease attributable in part to the induction of CD4 þ CD25 þ Foxp3 þ and CD8 þ Foxp3 þ regulatory T cells. We compared 45 000 murine genes in total white blood cells (WBC), CD4 þ T cells, and CD8 þ T cells from splenocytes of (NZBxNZW) F1 lupus-prone mice tolerized with pCons vs untreated naïve mice and found two-fold or greater differential expression for 448 WBC, 174 CD4, and 60 CD8 genes. We identified differentially expressed genes that played roles in the immune response and apoptosis. Using real-time PCR, we validated differential expression of selected genes (IFI202B, Bcl2, Foxp3, Trp-53, CCR7 and IFNar1) in the CD8 þ T cell microarray and determined expression of selected highly upregulated genes in different immune cell subsets. We also determined Smads expression in different immune cell subsets, including CD4 þ T cells and CD8 þ T cells, to detect the effects of TGF-b, known to be the major cytokine that accounts for the suppressive capacity of CD8 þ Treg in this system. Silencing of anti-apoptotic gene Bcl2 or interferon genes (IFI202b and IFNar1 in combination) in CD8 þ T cells from tolerized mice did not affect the expression of the other selected genes. However, silencing of Foxp3 reduced expression of Foxp3, Ifi202b and PD1-all of which are involved in the suppressive capacity of CD8 þ Treg in this model.

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“…The PRDX2 is a peroxidoreductase that catalyzes oxidation-reduction reactions and has been implicated in Down's syndrome [72], Alzheimer's disease [73] and various forms of neoplasms [74]. The protein may be involved in the regulation of apoptosis and response to oxidative stress [75], possibly by influencing oxidoreductase enzyme activities [67,69,76], among others. The CRYM has also been associated with various forms of cancer [77].…”

Section: Discussionmentioning

confidence: 99%

Left ventricular global transcriptional profiling in human end-stage dilated cardiomyopathy

et al. 2009

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We employed ABI high-density oligonucleotide microarrays containing 31,700 sixty-mer probes (representing 27,868 annotated human genes) to determine differential gene expression in idiopathic dilated cardiomyopathy (DCM). We identified 626 up-regulated and 636 down-regulated genes in DCM compared to controls. Most significant changes occurred in the tricarboxylic acid cycle, angiogenesis, and apoptotic signaling pathways, among which 32 apoptosis- and 13 MAPK activity-related genes were altered. Inorganic cation transporter, catalytic activities, energy metabolism and electron transport-related processes were among the most critically influenced pathways. Among the up-regulated genes were HTRA1 (6.9-fold), PDCD8(AIFM1) (5.2) and PRDX2 (4.4) and the down-regulated genes were NR4A2 (4.8), MX1 (4.3), LGALS9 (4), IFNA13 (4), UNC5D (3.6) and HDAC2 (3) (pb0.05), all of which have no clearly defined cardiac-related function yet. Gene ontology and enrichment analysis also revealed significant alterations in mitochondrial oxidative phosphorylation, metabolism and Alzheimer’s disease pathways. Concordance was also confirmed for a significant number of genes and pathways in an independent validation microarray dataset. Furthermore, verification by real-time RT-PCR showed a high degree of consistency with the microarray results. Our data demonstrate an association of DCM with alterations in various cellular events and multiple yet undeciphered genes that may contribute to heart muscle disease pathways.

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Downregulation of topoisomerase IIβ in myeloid leukemia cell lines leads to activation of apoptosis following all-trans retinoic acid-induced differentiation/growth arrest

Cited by 30 publications

References 25 publications

Roles of the C-terminal domains of topoisomerase IIα and topoisomerase IIβ in regulation of the decatenation checkpoint

Roles of the C-terminal domains of topoisomerase IIα and topoisomerase IIβ in regulation of the decatenation checkpoint

Distinct gene signature revealed in white blood cells, CD4+ and CD8+ T cells in (NZBx NZW) F1 lupus mice after tolerization with anti-DNA Ig peptide

Left ventricular global transcriptional profiling in human end-stage dilated cardiomyopathy

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