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Microtubules are dynamic structures that undergo cycles of catastrophe and rescue. The microtubules play a central role in cell division by forming the spindle apparatus for segregating the chromosomes. This makes them ideal targets for regulating dividing cells in tumors and malignant cancer cells. Microtubule stabilizing drugs help stabilize the microtubule formation and promote its polymerization. Paclitaxel was the first microtubule stabilizing agent used as anticancer drug in chemotherapy...
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Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
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Updated: May 16, 2025

Live Imaging to Study Microtubule Dynamic Instability in Taxane-resistant Breast Cancers
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GMCL1 Controls 53BP1 Stability and Modulates Paclitaxel Sensitivity in Cancer.

Yuki Kito1,2, Tania J Gonza Lez-Robles1,3,4, Sharon Kaisari1,2,4

  • 1Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA.

Biorxiv : the Preprint Server for Biology
|April 1, 2025
PubMed
Summary
This summary is machine-generated.

High GMCL1 expression drives paclitaxel resistance in cancers by degrading 53BP1, preventing mitotic stopwatch complex formation and promoting cell proliferation. GMCL1 inhibition may restore taxane sensitivity.

Keywords:
53BP1GMCL1mitotic stopwatchp53prolonged mitosisprotein degradationubiquitin

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Long-term Live-cell Imaging to Assess Cell Fate in Response to Paclitaxel
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Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Therapeutics

Background:

  • The Mitotic Surveillance Pathway (MSP) normally halts cell division during prolonged M-phase, involving the 53BP1, USP28, and p53 complex.
  • Paclitaxel resistance in cancer involves bypassing MSP, but mechanisms are unclear.
  • Understanding resistance is crucial for effective cancer treatment.

Purpose of the Study:

  • Investigate the mechanisms underlying paclitaxel resistance in cancers.
  • Identify novel therapeutic targets to overcome taxane resistance.

Main Methods:

  • Protein interaction studies to analyze 53BP1 and GMCL1 binding.
  • Ubiquitin ligase assays to determine CRL3GMCL1 activity on 53BP1.
  • Correlation analysis of GMCL1 expression with paclitaxel resistance in various cancer cell lines.
  • Functional studies assessing the impact of GMCL1 loss on drug sensitivity.

Main Results:

  • 53BP1 directly interacts with GMCL1, and CRL3GMCL1 targets 53BP1 for degradation during M-phase.
  • High GMCL1 expression correlates with paclitaxel resistance in p53 wild-type cancers (endometrial, breast, upper aerodigestive tract).
  • GMCL1 depletion restores paclitaxel sensitivity in p53-expressing cells.

Conclusions:

  • GMCL1 promotes paclitaxel resistance by mediating 53BP1 degradation, inhibiting the mitotic stopwatch complex, and allowing p53 degradation.
  • GMCL1 is a potential therapeutic target to re-sensitize resistant cancers to taxanes.