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Event: 1580

Key Event Title

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Binding of microtubule stabilizing agents (MSA) to microtubules

Short name
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Binding of MSAs to microtubules
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Biological Context

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Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

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AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Microtubule interacting drugs lead to peripheral neuropathy MolecularInitiatingEvent Arthur Author (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Sex Applicability

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Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

MSAs bind to polymerized tubulin. [1, 2] In several studies, MSAs were shown to inhibit cell proliferation and possess antineoplastic activity. [3-9] The taxane pocket found on the β-subunit of tubulin dimers was identified as the binding site for taxol and other MSAs like the above mentioned epothilones. [6-8, 10-20] Binding of MSAs is reversible. [6-8, 13-15]

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

- Electron microscopy of tannin-embedded tubulin crystals stabilized with taxol. Projection density maps were created from the electron microscopy data and further processed to difference maps of tubulin to visualize the binding site of taxol in polymerized tubulin [12, 16]

- Direct photolabeling of tubulin with radiolabelled [ 3 H]taxol [13], and [ 3 H]taxoid-derivatives to identify binding sites of taxol in tubulin [10, 11, 14, 15, 18]

- Mapping studies: Tubulin is photolabelled with [ 3 H]taxoid-derivatives. To identify the photoincorporation site, the labelled complex is then digested by formic acid or CNBr in combination with either clostripain or trypsin. The obtained peptide fragments are analysed via reverse phase HPLC and the radioactive peak is sequenced. [14, 15, 18]

- X-ray crystallography [17]

- NMR studies [20] and solid-state rotational echo double-resonance (REDOR) NMR [19] to determine the orientation of microtubule-bound taxol

- Fluorescence energy transfer (FRET) spectroscopy to determine the conformation of microtubule-bound taxol [19]

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

References

List of the literature that was cited for this KE description. More help

1. Manfredi, J.J., J. Parness, and S.B. Horwitz, Taxol binds to cellular microtubules. The Journal of Cell Biology, 1982. 94(3): p. 688-696. Confidential

2. Parness, J. and S. Horwitz, Taxol binds to polymerized tubulin in vitro. The Journal of Cell Biology, 1981. 91(2): p. 479-487.

3. Riondel, J., et al., Therapeutic response to taxol of six human tumors xenografted into nude mice. Cancer Chemotherapy and Pharmacology, 1986. 17(2): p. 137-142.

4. Wani, M.C., et al., Plant antitumor agents. VI. Isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. Journal of the American Chemical Society, 1971. 93(9): p. 2325-2327.

5. Schiff, P.B., J. Fant, and S.B. Horwitz, Promotion of microtubule assembly in vitro by taxol. Nature, 1979. 277(5698): p. 665-667.

6. Bollag, D.M., et al., Epothilones, a New Class of Microtubule-stabilizing Agents with a Taxol-like Mechanism of Action. Cancer Research, 1995. 55(11): p. 2325-2333.

7. Hung, D.T., J. Chen, and S.L. Schreiber, (+)-Discodermolide binds to microtubules in stoichiometric ratio to tubulin dimers, blocks taxol binding and results in mitotic arrest. Chemistry & Biology, 1996. 3(4): p. 287-293.

8. Kowalski, R.J., et al., The Microtubule-Stabilizing Agent Discodermolide Competitively Inhibits the Binding of Paclitaxel (Taxol) to Tubulin Polymers, Enhances Tubulin Nucleation Reactions More Potently than Paclitaxel, and Inhibits the Growth of Paclitaxel-Resistant Cells. Molecular Pharmacology, 1997. 52(4): p. 613-622.

9. ter Haar, E., et al., Discodermolide, A Cytotoxic Marine Agent That Stabilizes Microtubules More Potently Than Taxol. Biochemistry, 1996. 35(1): p. 243-250.

10. Combeau, C., et al., Predominant Labeling of. beta.-over. alpha.-Tubulin from Porcine Brain by a Photoactivatable Taxoid Derivative. Biochemistry, 1994. 33(21): p. 6676-6683. Confidential

11. Dasgupta, D., et al., Synthesis of a photoaffinity taxol analog and its use in labeling tubulin. Journal of medicinal chemistry, 1994. 37(18): p. 2976-2980.

12. Nogales, E., S.G. Wolf, and K.H. Downing, Structure of the αβ tubulin dimer by electron crystallography. Nature, 1998. 391: p. 199.

13. Rao, S., S.B. Horwitz, and I. Ringel, Direct Photoaffinity Labeling of Tubulin With Taxol. JNCI: Journal of the National Cancer Institute, 1992. 84(10): p. 785-788.

14. Rao, S., et al., 3'-(p-azidobenzamido)taxol photolabels the N-terminal 31 amino acids of beta-tubulin. Journal of Biological Chemistry, 1994. 269(5): p. 3132-3134.

15. Rao, S., et al., Characterization of the Taxol Binding Site on the Microtubule 2-(m-AZIDOBENZOYL) TAXOL PHOTOLABELS A PEPTIDE (AMINO ACIDS 217-231) of β-TUBULIN. Journal of Biological Chemistry, 1995. 270(35): p. 20235-20238.

16. Nogales, E., et al., Structure of tubulin at 6.5 Å and location of the taxol-binding site. Nature, 1995. 375(6530): p. 424-427.

17. Prota, A.E., et al., Molecular mechanism of action of microtubule-stabilizing anticancer agents. Science, 2013. 339(6119): p. 587-590.

18. Rao, S., et al., Characterization of the Taxol Binding Site on the Microtubule: IDENTIFICATION OF Arg282 IN β-TUBULIN AS THE SITE OF PHOTOINCORPORATION OF A 7-BENZOPHENONE ANALOGUE OF TAXOL. Journal of Biological Chemistry, 1999. 274(53): p. 37990-37994.

19. Li, Y., et al., Conformation of Microtubule-Bound Paclitaxel Determined by Fluorescence Spectroscopy and REDOR NMR. Biochemistry, 2000. 39(2): p. 281-291.

20. Snyder, J.P., et al., The binding conformation of Taxol in β-tubulin: A model based on electron crystallographic density. Proceedings of the National Academy of Sciences, 2001. 98(9): p. 5312-5316.