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‖ and
- Jay Wimalasena‡**
- From the ‡Department of Obstetrics and Gynecology, Graduate School of Medicine, University of Tennessee Medical Center, Knoxville, Tennessee 37920, the §Department of Obstetrics and Gynecology, Chang-Gung Medical School, Chang-Gung Memorial Hospital, Taipei, Taiwan, the ¶Department of Biochemistry, the Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 170, Japan, and the ‖Medicine Branch, Division of Clinical Sciences, NCI, National Institutes of Health, Bethesda, Maryland 20892
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.
Footnotes
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↵* This work was supported by National Institutes of Health Grants AA-08328 and CA-68538 (to J. W.) and Chang-Gung Memorial Hospital Research Grant CMRP-0426 (to H.-S. W.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵** To whom correspondence should be addressed: Dept. of Obstetrics and Gynecology, University of Tennessee Medical Center, 1924 Alcoa Hwy., Knoxville, TN 37920. Tel.: 423-544-8960; Fax: 423-544-6863; E-mail:mcf7{at}msn.com.
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↵1 The abbreviations used are: JNK, c-Jun N-terminal kinase; MIA, microtubule-interfering agent; SAPK, stress-activated protein kinase; ASK1, apoptosis signal-regulating kinase; TPA, 12-O-tetradecanoylphorbol-13-acetate; TRE, TPA response element; CAT, chloramphenicol acetyltransferase; dn, dominant-negative; JNKK/SEK1, JNK kinase/SAPK or ERK kinase; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; LPS, lipopolysaccharide; HA, hemagglutinin epitope of influenza virus; GST, glutathione S-transferase; RBD, Ras-binding domain of Raf-1; FBS, fetal bovine serum; DMEM, Dulbecco’s modified Eagle’s medium; MBP, myelin basic protein; ARIA, activated Ras interaction assay; PAGE, polyacrylamide gel electrophoresis.
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↵2 H. Ichijo, unpublished data.
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↵3 The inhibitory efficacy of the expression vector for dn Ras used in this study was verified by cotransfection experiments with HA-tagged ERK2, where the dn Ras completely blocked activation of HA-ERK2 by treatment with epidermal growth factor (T.-H. Wang, unpublished data).
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- Received September 9, 1997.
- Revision received November 12, 1997.
- The American Society for Biochemistry and Molecular Biology, Inc.
