Colchicine Effect on the Mitotic Spindle: Estimate of Multipolar Anaphase Production

Hervás, J. P.; Fernández-Gómez, M. E.; Giménez-Martín, G.

doi:10.1080/00087114.1974.10796589

Cited by 7 publications

(4 citation statements)

References 14 publications

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“…6e). Multiple studies have shown that Colchicine disrupts the metaphase to anaphase transition (see for example, (54)), yet, the increase in anaphase has also been documented (55). Furthermore, it is established that different cell types behave differently during mitosis in the presence of drugs that disrupt microtubules function (56).…”

Section: Resultsmentioning

confidence: 99%

The TRF2 General Transcription Factor Is a Key Regulator of Cell Cycle Progression

Kedmi

Sloutskin

Epstein

et al. 2020

Preprint

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26Background: Diverse biological processes and transcriptional programs are 27 regulated by RNA polymerase II (Pol II), which is recruited by the general transcription 28 machinery to the core promoter to initiate transcription. TRF2 (TATA-box-binding 29 protein-related factor 2) is an evolutionarily conserved general transcription factor that 30 is essential for embryonic development of Drosophila melanogaster, C. elegans, 31 zebrafish and Xenopus. Nevertheless, the cellular processes that are regulated by 32 TRF2 are largely underexplored. 33Results: Here, using Drosophila Schneider cells as a model, we discovered that TRF2 34 regulates apoptosis and cell cycle progression. We show that TRF2 knockdown 35 results in increased expression of distinct pro-apoptotic genes and induces apoptosis. 36Using flow cytometry, high-throughput microscopy and advanced imaging-flow 37 cytometry, we demonstrate that TRF2 regulates cell cycle progression and exerts 38 distinct effects on G1 and specific mitotic phases. RNA-seq analysis revealed that 39 TRF2 controls the expression of Cyclin E and the mitotic cyclins, Cyclin A, Cyclin B 40 and Cyclin B3, but not Cyclin D or Cyclin C. To identify proteins that could account for 41 the observed regulation of these cyclin genes, we searched for TRF2-interacting 42 proteins. Interestingly, mass spectrometry analysis of TRF2-containing complexes 43 identified GFZF, a nuclear glutathione S-transferase implicated in cell cycle regulation, 44and Motif 1 binding protein (M1BP). TRF2 has previously been shown to interact with 45 M1BP and M1BP has been shown to interact with GFZF. Furthermore, available ChIP-46 exo data revealed that TRF2, GFZF and M1BP co-occupy the promoters of TRF2-47 with TRF2, it is TRF2, rather than GFZF or M1BP, that is the main factor regulating 50 the expression of Cyclin E and the mitotic cyclins. 51 Conclusions: Our findings uncover a critical and unanticipated role of a general 52 transcription factor as a key regulator of cell cycle and apoptosis. 53 54 Keywords 55 Basal transcription machinery, RNA polymerase II, gene expression, TATA box-56 binding protein (TBP), TBP-related factor 2 (TRF2), cyclin genes. 57 58 BACKGROUND 59 Multiple biological processes and transcriptional programs are regulated by RNA 60 polymerase II (Pol II). The initiation of transcription of protein-coding genes and 61 distinct non-coding RNAs occurs following the recruitment of Pol II to the core 62 promoter region by the general/basal transcription machinery (1-4). The core 63promoter, which directs accurate initiation of transcription and encompasses the 64 transcription start site (TSS), may contain short DNA sequence elements/motifs, 65 which confer specific properties to the core promoter (1, 4-10). The first step in the 66 recruitment of Pol II to initiate transcription is the binding of TFIID, which is 67 composed of TATA-box-binding protein (TBP) and TBP-associated factors. 68Remarkably, although TBP is considered a universal general transcription factor, 69 robust Pol II transc...

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Section: Resultsmentioning

confidence: 99%

The TRF2 General Transcription Factor Is a Key Regulator of Cell Cycle Progression

Kedmi

Sloutskin

Epstein

et al. 2020

Preprint

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“…Nocodazole [ 88 ] and colcemid [ 92 ] bind to the colchicine site on tubulin, while paclitaxel, docetaxel, and epothilones bind to the taxane site [ 93 , 94 ], and vinca alkaloids and eribulin bind to the vinca domain [ 91 ]. However, colchicine has been reported to potently induce multipolar spindles at certain concentrations [ 95 ]. Interestingly, colchicine binding to tubulin is poorly reversible [ 21 , 96 ], while nocodazole [ 88 ] and colcemid [ 97 , 98 ] binding is rapidly reversible.…”

Section: Discussionmentioning

confidence: 99%

Diverse microtubule-targeted anticancer agents kill cells by inducing chromosome missegregation on multipolar spindles

Zhou,

Tucker,

Scribano

et al. 2023

PLoS Biol

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Microtubule-targeted agents are commonly used for cancer treatment, though many patients do not benefit. Microtubule-targeted drugs were assumed to elicit anticancer activity via mitotic arrest because they cause cell death following mitotic arrest in cell culture. However, we recently demonstrated that intratumoral paclitaxel concentrations are insufficient to induce mitotic arrest and rather induce chromosomal instability (CIN) via multipolar mitotic spindles. Here, we show in metastatic breast cancer and relevant human cellular models that this mechanism is conserved among clinically useful microtubule poisons. While multipolar divisions typically produce inviable progeny, multipolar spindles can be focused into near-normal bipolar spindles at any stage of mitosis. Using a novel method to quantify the rate of CIN, we demonstrate that cell death positively correlates with net loss of DNA. Spindle focusing decreases CIN and causes resistance to diverse microtubule poisons, which can be counteracted by addition of a drug that increases CIN without affecting spindle polarity. These results demonstrate conserved mechanisms of action and resistance for diverse microtubule-targeted agents. Trial registration: clinicaltrials.gov, NCT03393741.

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“…The main target of carbamates seems to be not the microtubule itself but the MTOCs in mitosis. It is possible to induce abnormal poles either directly with carbamates (Coss and Pickett-Heaps 1974, Coss et al 1975, Oliver et al 1978, Gim6nez-Abifin et al 1997 or indirectly with c-mitotic agents, either colchicine (Hervfis et al 1974) or 7-hexachlorocyclohexane (Hervfis and Gimdnez-Martfn 1974). All these drugs give rise to the formation of either a single cell with tetraploid DNA content or to three or four cells derived from a single metaphase.…”

Section: Introductionmentioning

confidence: 97%

Immediate disruption of spindle poles and induction of additional microtubule-organizing centres by a phenylcarbamate, during plant mitosis

et al. 1998

Self Cite

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Summary. The herbicide carbetamide [(R)-l-(ethylcarbamoyl) ethylphenylcarbamate], in the 0.4 to 0.8 mM range, efficiently induced multipolar mitoses in Allium cepa L. The frequency of multipolar anaphases rose earlier and reached higher values when both concentration and time of treatment increased, up to a maximum of 90% after 1 h of treatment. To identify the physiological target, the kinetics of induction of multipolar mitoses were followed during recovery from very short treatments (5, 10, and 15 min). Tubulin immunodetection showed that phenylcmbamate immediately disrupts the cohesion between the different bundles of microtubule minus ends which converge at the pole. The spindle was rendered multipolar about three times more efficiently in metaphase than in anaphase. The observations do not support any effect of the herbicide on the tubulin polymerization-depolymerization cycle, and suggest that the minus ends of the microtubules remained stabilized in carbetamide. Thus, the density of kinetochore microtubnles and their lengths were unmodified in the individual chromosomes which became detached from both spindle poles in response to the herbicide. Extra microtubule-organizing centres for the assembly of both preprophase band and phragmoplast (the tubulin arrays which characterize the microtubular cycle responsible for cytokinesis in plant cells) were also rapidly induced.

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Colchicine Effect on the Mitotic Spindle: Estimate of Multipolar Anaphase Production

Cited by 7 publications

References 14 publications

The TRF2 General Transcription Factor Is a Key Regulator of Cell Cycle Progression

The TRF2 General Transcription Factor Is a Key Regulator of Cell Cycle Progression

Diverse microtubule-targeted anticancer agents kill cells by inducing chromosome missegregation on multipolar spindles

Immediate disruption of spindle poles and induction of additional microtubule-organizing centres by a phenylcarbamate, during plant mitosis

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