Targeting the Microtubular Network as a New Antimyeloma Strategy

Feng, Rentian; Liu, Shirong; Lu, Chang; Andreas, Carrie; Stolz, Donna B.; Mapara, Markus Y.; Lentzsch, Suzanne

doi:10.1158/1535-7163.mct-11-0234

Cited by 23 publications

(23 citation statements)

References 39 publications

(39 reference statements)

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“…We arrested human HeLa cells with a double thymidine block followed by nocodazole treatment and shake-off (Figure 1A) (Whitfield et al, 2002). This method results in a highly pure population of early mitotic cells (prophase/prometaphase) (Feng et al, 2011) as assessed by anti-histone H3 phosphorylated-serine 10 (phH3S10) (Figure S1A), 5-ethynyl-2′-deoxyuridine (EdU), and 7-Aminoactinomycin D (7-AAD) staining (Figure 1B). ChIP-Seq of H3K4me3 and TFIIB demonstrates that H3K4me3 is still present on the mitotic chromosomes while TFIIB occupancy is dramatically reduced (Figures 1C and 1D), although bulk TFIIB protein levels are not decreased during early mitosis (Figure S1A).…”

Section: Resultsmentioning

confidence: 99%

Mitotic Transcriptional Activation: Clearance of Actively Engaged Pol II via Transcriptional Elongation Control in Mitosis

et al. 2015

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Summary Although it is established that some general transcription factors are inactivated at mitosis, many details of Mitotic Inhibition of Transcription (MIT) and its underlying mechanisms are largely unknown. We have identified Mitotic Transcriptional Activation (MTA) as a key regulatory step to control transcription in mitosis for genes with transcriptionally engaged RNA Polymerase II (Pol II) to activate and transcribe until the end of the gene to clear Pol II from mitotic chromatin, followed by global impairment of transcription reinitiation through MIT. Global nascent RNA sequencing and RNA fluorescence in situ hybridization demonstrate the existence of transcriptionally engaged Pol II in early mitosis. Both genetic and chemical inhibition of P-TEFb in mitosis lead to delays in the progression of cell division. Together, our study reveals a mechanism for MTA and MIT whereby transcriptionally engaged Pol II can progress into productive elongation and finish transcription to allow proper cellular division.

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Section: Resultsmentioning

confidence: 99%

Mitotic Transcriptional Activation: Clearance of Actively Engaged Pol II via Transcriptional Elongation Control in Mitosis

et al. 2015

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“…Western blotting was conducted as previously described [24]. Briefly, cells were harvested, lysed with radioimmunoprecipitation assay buffer (Pierce) containing phosphatase and protease inhibitors (Halt Protease Inhibitor Cocktail Kit; Pierce).…”

Section: Methodsmentioning

confidence: 99%

Antagonism of cannabinoid receptor 2 pathway suppresses IL-6-induced immunoglobulin IgM secretion

Feng

Milcarek

Xie

2014

BMC Pharmacol Toxicol

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BackgroundCannabinoid receptor 2 (CB2) is expressed predominantly in the immune system, particularly in plasma cells, raising the possibility that targeting the CB2 pathway could yield an immunomodulatory effect. Although the role of CB2 in mediating immunoglobulin class switching has been reported, the effects of targeting the CB2 pathway on immunoglobulin secretion per se remain unclear.MethodsHuman B cell line SKW 6.4, which is capable of differentiating into IgM-secreting cells once treated with human IL-6, was employed as the cell model. SKW 6.4 cells were incubated for 4 days with CB2 ligands plus IL-6 (100 U/ml). The amount of secreted IgM was determined by an ELISA. Cell proliferation was determined by the 3H-Thymidine incorporation assay. Signal molecules involved in the modulation of IgM secretion were examined by real-time RT-PCR and Western blot analyses or by using their specific inhibitors.ResultsWe demonstrated that CB2 inverse agonists SR144528 and AM630, but not CB2 agonist HU308 or CB1 antagonist SR141716, effectively inhibited IL-6-induced secretion of soluble IgM without affecting cell proliferation as measured by thymidine uptake. SR144528 alone had no effects on the basal levels of IgM in the resting cells. These effects were receptor mediated, as pretreatment with CB2 agonist abrogated SR144528-mediated inhibition of IL-6 stimulated IgM secretion. Transcription factors relevant to B cell differentiation, Bcl-6 and PAX5, as well as the protein kinase STAT3 pathway were involved in the inhibition of IL-6-induced IgM by SR144528.ConclusionsThese results uncover a novel function of CB2 antagonists and suggest that CB2 ligands may be potential modulators of immunoglobulin secretion.

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“…Drugs targeting cytoskeleton components may be antitumoral and antiparasitic [35][36][37][38][39]. Microtubule or microfilament-targeting drugs may be used for selecting multidrug resistant phenotypes in both cancer cells and parasites [40][41][42][43].…”

Section: Discussionmentioning

confidence: 99%

Modes of Action of Arjunolic Acid and Derivatives on Trypanosoma cruzi Cells

Souza-Neta¹,

Menezes²,

Lima³

et al. 2014

CTMC

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Chagas disease causes considerable morbimortality in the Americas, with circa 7 to 8 million infected people, causing at least 12,000 annual deaths and 100 million people at risk. Its chemotherapy is poorly selective and effective, associated to severe side effects and unresponsive cases. Thus, R&D on therapeutic alternatives is undoubtedly required. The Brazilian poorly studied biodiversity offers uncountable bioagents, which may be exploited for chemotherapy. The triterpene arjunolic acid (AA), reduced the Trypanosoma cruzi epimastigote in vitro proliferation with an apparent IC₅₀ of 171 µM. Electron microscopy analysis revealed remarkable effects on the parasite surface and architecture. AA-treated parasites displayed minutely corrugated plasma membranes devoid of subpellicular microtubules as well as biogenesis of multiple basal bodies. As the AA effects appeared mainly restricted or originated at the parasite peripheral cytoplasm, including the cytoskeleton membrane linkage, we inferred that the compound targeted primarily the lipid bilayer; therefore, we performed synthetic modification to increase the molecule lipophilicity and thus membrane permeability. The methyl ester (MeAA) and tri-acetylated derivatives (3AcAA) had potentiated trypanocidal activity, producing IC₅₀ values of 21.9 and 15.8 µM, respectively. Both derivatives were able to produce remarkable ultrastructural alterations in the parasites, including inner compartments such as Golgi apparatus and the endocytic/autophagic pathway. Parasites cultured with both derivatives displayed numerous and large autophagic vacuoles, altered flagellar length and cell body connection. These data indicate that synthetically-modified natural products comprise valuable tools in antiparasitic chemotherapy and that electron microscopy may be useful not only in determining the mechanisms of action but also in directing such modifications for rational drug design.

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Targeting the Microtubular Network as a New Antimyeloma Strategy

Cited by 23 publications

References 39 publications

Mitotic Transcriptional Activation: Clearance of Actively Engaged Pol II via Transcriptional Elongation Control in Mitosis

Mitotic Transcriptional Activation: Clearance of Actively Engaged Pol II via Transcriptional Elongation Control in Mitosis

Antagonism of cannabinoid receptor 2 pathway suppresses IL-6-induced immunoglobulin IgM secretion

Modes of Action of Arjunolic Acid and Derivatives on Trypanosoma cruzi Cells

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