Identification of the site of inhibition of oncogenic ras-p21-induced signal transduction by a peptide from a ras effector domain.
We have previously found that a peptide corresponding to residues 35-47 of the ras-p21 protein, from its switch 1 effector domain region, strongly inhibits oocyte maturation induced by oncogenic p21, but not by insulin-activated cellular wild-type p21. Another ras-p21 peptide corresponding to residues 96-110 that blocks ras-jun and jun kinase (JNK) interactions exhibits a similar pattern of inhibition. We have also found that c-raf strongly induces oocyte maturation and that dominant negative c-raf strongly blocks oncogenic p21-induced oocyte maturation. We now find that the p21 35-47, but not the 96-110, peptide completely blocks c-raf-induced maturation. This finding suggests that the 35-47 peptide blocks oncogenic ras at the level of raf; that activated normal and oncogenic ras-p21 have differing requirements for raf-dependent signaling; and that the two oncogenic-ras-selective inhibitory peptides, 35-47 and 96-110, act at two different critical downstream sites, the former at raf the latter at JNK/jun, both of which are required for oncogenic ras-p21 signaling.
Chie
L
L
Department of Pathology and Laboratory Medicine, Harbor VA Medical Center, Brooklyn, New York 11209, USA.
Chen
J M
JM
Friedman
F K
FK
Chung
D L
DL
Amar
S
S
Michl
J
J
Yamaizumi
Z
Z
Brandt-Rauf
P W
PW
Pincus
M R
MR
D000818:Animals; D005260:Female; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009865:Oocytes / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism*
D007328:Insulin; D010446:Peptide Fragments; D019908:Proto-Oncogene Proteins c-raf; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D015689:Oncogene Protein p21(ras); D018631:ras Proteins