Microtubule-interfering Agents Activate c-Jun N-terminal Kinase/Stress-activated Protein Kinase through Both Ras and Apoptosis Signal-regulating Kinase Pathways

Tzu-Hao Wang, Hsin-Shih Wang, Hidenori Ichijo, Paraskevi Giannakakou, James S. Foster, Tito Fojo, Jay Wimalasena
1998 Journal of Biological Chemistry  
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 G 2 /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
more » ... d 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-Otetradecanoylphorbol-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. c-Jun N-terminal kinases (JNKs), 1 also known as stress-
doi:10.1074/jbc.273.9.4928 pmid:9478937 fatcat:so5uhjvngjajzdjs5zgh2vitpy