Microtubule-interfering agents activate c-Jun N-terminal kinase/stress- activated protein kinase through both Ras and apoptosis signal-regulating kinase pathways Academic Article Article uri icon

Overview

MeSH Major

  • Financing, Organized
  • Medical Oncology
  • National Institutes of Health (U.S.)
  • Neoplasms
  • Research Support as Topic
  • Training Support

abstract

  • The essential cellular functions associated with microtubules have led to a wide use of microtubule-interfering agents in cancer chemotherapy with promising results. Although the most well studied action of microtubule-interfering agents is an arrest of cells at the G2/M phase of the cell cycle, other effects may also exist. We have observed that paclitaxel (Taxol), docetaxel (Taxotere), vinblastine, vincristine, nocodazole, and colchicine activate the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) signaling pathway in a variety of human cells. Activation of JNK/SAPK by microtubule-interfering agents is dose-dependent and time-dependent and requires interactions with microtubules. Functional activation of the JNKK/SEK1-JNK/SAPK-c-Jun cascade (where JNKK/SEK1 is JNK kinase/SAPK kinase) was demonstrated by activation of a 12-O-tetradecanoylphorbol-13-acetate response element (TRE) reporter construct in a c-Jun dependent fashion. Microtubule-interfering agents also activated both Ras and apoptosis signal-regulating kinase (ASK1) and coexpression of dominant negative Ras and dominant negative apoptosis signal-regulating kinase exerted individual and additive inhibition of JNK/SAPK activation by microtubule-interfering agents. These findings suggest that multiple signal transduction pathways are involved with cellular detection of microtubular disarray and subsequent activation of JNK/SAPK.

publication date

  • February 27, 1998

Research

keywords

  • Academic Article

Identity

Digital Object Identifier (DOI)

  • 10.1074/jbc.273.9.4928

PubMed ID

  • 9478937

Additional Document Info

start page

  • 4928

end page

  • 36

volume

  • 273

number

  • 9