@article{ed5f5db95a36430e8fb138ea551c42e5,
title = "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",
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.",
keywords = "Dominant negative mutant of raf, Oncogenic ras-p21, Oocyte maturation",
author = "L. Chie and S. Amar and Kung, \{H. F.\} and Lin, \{M. C.M.\} and H. Chen and Chung, \{D. L.\} and V. Adler and Z. Ronai and Friedman, \{F. K.\} and Robinson, \{R. C.\} and C. Kovac and Brandt-Rauf, \{P. W.\} and Z. Yamaizumi and J. Michl and Pincus, \{M. R.\}",
note = "Funding Information: Fig. 6 Summary of proposed pathway elements of the oncogenic (p21*, left side of figure) and activated normal ras-p21 (right side of figure) proteins. Both oncogenic and normal proteins depend on raf. Since MKP-T4, the MAP kinase phosphatase, inhibits oncogenic more than activated normal p21, two arrows from raf have been drawn, one dashed to MEK, indicating that this is one of a number of possible targets for c-ras-activated raf and the rightmost (large) arrow from raf indicating other pathways that may be activated by raf (box with question mark). The leftmost arrow from raf shows that activation of MEK by raf is the unique pathway induced by oncogenic p21. Since activated normal p21 has been found to require activation of cyclins, the latter proteins are shown to be essential to the signal transduction pathway induced by this protein [10]. Oncogenic p21 requires jun-N-terminal kinase (JNK) [21] which, reciprocally, requires activation of raf (circled 1 in figure). Similarly, JNK reciprocally requires protein kinase C (PKC; circled 2 in figure) [25]. Finally PKC and raf interact in a mutually dependent manner (circled 3 in figure). Activation of jun and fos by JNK and mitogen-activated protein (MAP) kinase on the stress-activated and raf-MEK-MAP kinase pathways, respectively, results in the formation of the heterodimeric AP-1 complex Acknowledgements We are grateful to Novartis Pharma in Basel, Switzerland for the generous gifts of the compounds CGP 41 251 and CGP 42 700. This work was supported in part by NIH Grant CA 42500 (MRP) and CA 69243 (PWB-R), a VA Merit Review Grant (MRP), and EPA Grants R8825361 and R826685 (PWB-R). DLC thanks the Research Release Time Committee and the trustees of Long Island University for the Release Time Award to work on this project.",
year = "2000",
doi = "10.1007/s002800051017",
language = "English",
volume = "45",
pages = "441--449",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer Science and Business Media Deutschland GmbH",
number = "6",
}