Microtubule-interfering agents activate c-Jun N-terminal kinase/stress-activated protein kinase through both Ras and

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T H Wang1, H S Wang, H Ichijo

  • 1Department of Obstetrics and Gynecology, Graduate School of Medicine, University of Tennessee Medical Center, Knoxville, Tennessee 37920, USA.

The Journal of Biological Chemistry
|March 28, 1998
PubMed

Insights

Microtubule-interfering agents, used in cancer therapy, activate the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) pathway. This activation involves Ras and apoptosis signal-regulating kinase (ASK1), suggesting complex cellular responses to microtubule disruption.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Signal Transduction

Background:

  • Microtubule-interfering agents are crucial in cancer chemotherapy.
  • Their primary known action is cell cycle arrest at G2/M phase.
  • Potential alternative cellular effects are under investigation.

Purpose of the Study:

  • To investigate the effects of microtubule-interfering agents beyond cell cycle arrest.
  • To explore the activation of signaling pathways by these agents.
  • To identify the specific pathways involved in cellular response to microtubule disruption.

Main Methods:

  • Treatment of human cells with various microtubule-interfering agents (paclitaxel, docetaxel, vinblastine, vincristine, nocodazole, colchicine).
  • Assessment of c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) pathway activation.
  • Use of reporter constructs to demonstrate functional activation of the JNKK/SEK1-JNK/SAPK-c-Jun cascade.
  • Investigation of the roles of Ras and apoptosis signal-regulating kinase (ASK1) in JNK/SAPK activation.

Main Results:

  • Paclitaxel, docetaxel, vinblastine, vincristine, nocodazole, and colchicine activate the JNK/SAPK pathway in human cells.
  • JNK/SAPK activation is dose-dependent, time-dependent, and requires microtubule interaction.
  • The JNKK/SEK1-JNK/SAPK-c-Jun cascade is functionally activated.
  • Ras and ASK1 are activated by these agents and contribute to JNK/SAPK activation.

Conclusions:

  • Microtubule-interfering agents trigger the JNK/SAPK signaling pathway.
  • Ras and ASK1 are key components in the cellular detection of microtubule damage.
  • These findings reveal multifaceted signaling responses to microtubule disruption in cancer cells.

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