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: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biology, Long Island University, Brooklyn, NY 11201, USA.
authors.forename: L
authors.initials: L
authors.lastname: Chie
authors.forename: S
authors.initials: S
authors.lastname: Amar
authors.forename: H F
authors.initials: HF
authors.lastname: Kung
authors.forename: M C
authors.initials: MC
authors.lastname: Lin
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.forename: D L
authors.initials: DL
authors.lastname: Chung
authors.forename: V
authors.initials: V
authors.lastname: Adler
authors.forename: Z
authors.initials: Z
authors.lastname: Ronai
authors.forename: F K
authors.initials: FK
authors.lastname: Friedman
authors.forename: R C
authors.initials: RC
authors.lastname: Robinson
authors.forename: C
authors.initials: C
authors.lastname: Kovac
authors.forename: P W
authors.initials: PW
authors.lastname: Brandt-Rauf
authors.forename: Z
authors.initials: Z
authors.lastname: Yamaizumi
authors.forename: J
authors.initials: J
authors.lastname: Michl
authors.forename: M R
authors.initials: MR
authors.lastname: Pincus
mesh_terms: D000818:Animals; D005260:Female; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D009865:Oocytes / Q000254:growth & development*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D015398:Signal Transduction; D014982:Xenopus laevis
chemical_list: D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras)