Induction of oocyte maturation by jun-N-terminal kinase (JNK) on the oncogenic ras-p21 pathway is dependent on the raf-MEK signal transduction pathway

L. Chie, S. Amar, H. F. Kung, M. C.M. Lin, H. Chen, D. L. Chung, V. Adler, Z. Ronai, F. K. Friedman, R. C. Robinson, C. Kovac, P. W. Brandt-Rauf, Z. Yamaizumi, J. Michl, M. R. Pincus

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Purpose: We have previously found that microinjection of activated MEK (mitogen activated kinase kinase) and ERK (mitogen-activated protein; MAP kinase) fails to induce oocyte maturation, but that maturation, induced by oncogenic ras-p21 and insulin-activated cell ras-p21, is blocked by peptides from the ras-binding domain of raf. We also found that jun kinase (JNK), on the stress-activated protein (SAP) pathway, which is critical to the oncogenic ras-p21 signal transduction pathway, is a strong inducer of oocyte maturation. Our purpose in this study was to determine the role of the raf- MEK-MAP kinase pathway in oocyte maturation and how it interacts with JNK from the SAP pathway. Methods: We microinjected raf dominant negative mutant mRNA (DN-raf) and the MEK-specific phosphatase, MKP-T4, either together with oncogenic p21 or c-raf mRNA, into oocytes or into oocytes incubated with insulin to determine the effects of these raf-MEK-MAP kinase pathway inhibitors. Results: We found that oocyte maturation induced by both oncogenic and activated normal p21 is inhibited by both DN-raf and by MKP-T4. The latter more strongly blocks the oncogenic pathway. Also an mRNA encoding a constitutively activated MEK strongly induces oocyte maturation that is not inhibited by DN-raf or by MKP-T4. Surprisingly, we found that oocyte maturation induced by JNK is blocked both by DN-raf and MKP-T4. Furthermore, we discovered that c-raf induces oocyte maturation that is inhibited by glutathione-S-transferase (GST), which we have found to be a potent and selective inhibitor of JNK. Conclusion: We conclude that there is a strong reciprocal interaction between the SAP pathway involving JNK and the raf-MEK- MAP kinase pathway and that oncogenic ras-p21 can be preferentially inhibited by MEK inhibitors. The results imply that blockade of both MEK and JNK- oncogenic ras-p21 interactions may constitute selective synergistic combination chemotherapy against oncogenic ras-induced tumors.

Original languageEnglish
Pages (from-to)441-449
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Volume45
Issue number6
DOIs
StatePublished - 2000

Keywords

  • Dominant negative mutant of raf
  • Oncogenic ras-p21
  • Oocyte maturation

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