Evidence that oocyte maturation induced by an oncogenic ras-p21 protein and insulin is mediated by overlapping yet distinct mechanisms.
We have recently shown that a peptide (residues 35-47) from a functional region of the ras p21 protein, thought to be involved in the binding of p21 to GTPase activating protein, the antibiotic azatyrosine, known to induce the ras-recision gene, and the selective protein kinase C inhibitor, CGP 41,251, all inhibit oncogenic p21 protein-induced maturation of oocytes in a dose-dependent manner. We now show that these three agents only partially inhibit insulin-induced oocyte maturation, known to be dependent on activation of cellular p21 protein. On the other hand, the anti-p21 protein antibody Y13-259 completely inhibits both insulin- and oncogenic p21 protein-induced maturation as does a tetrapeptide, CVIM, known to block the enzyme farnesyl transferase which covalently attaches the farnesyl moiety to the p21 protein allowing it to attach to the cell membrane. Our results suggest that while the oncogenic and insulin-activated normal p21 proteins share certain elements of their signal transduction pathways in common, these pathways diverge and allow for selective inhibition of the oncogenic pathway.
Chung
D L
DL
Department of Chemistry, New York University, New York 10003.
Joran
A
A
Friedman
F
F
Robinson
R
R
Brandt-Rauf
P W
PW
Weinstein
I B
IB
Ronai
Z
Z
Baskin
L
L
Dykes
D C
DC
Murphy
R B
RB
D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000470:Alkaloids / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D007328:Insulin / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology; D015689:Oncogene Protein p21(ras) / Q000494:pharmacology*; D009865:Oocytes / Q000166:cytology / Q000187:drug effects*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D017368:Protein Prenylation; D015398:Signal Transduction; D019311:Staurosporine / Q000031:analogs & derivatives*; D014982:Xenopus laevis
D000470:Alkaloids; D007328:Insulin; D009842:Oligopeptides; C011870:beta-(5-hydroxy-2-pyridyl)alanine; D011493:Protein Kinase C; D015689:Oncogene Protein p21(ras); D019311:Staurosporine; C059539:midostaurin; D000409:Alanine