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Evidence that oocyte maturation induced by an oncogenic ras-p21 protein and insulin is mediated by overlapping yet
D L Chung1, A Joran, F Friedman
1Department of Chemistry, New York University, New York 10003.
Abstract:
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.
Insights
Oncogenic ras p21 protein and normal cellular p21 protein pathways diverge. Specific inhibitors block oncogenic pathways, suggesting targeted cancer therapies.
Area of Science:
- Molecular Biology
- Cell Signaling
- Oncology
Background:
- The ras p21 protein plays a crucial role in cellular signaling pathways.
- Dysregulation of ras p21 is implicated in various cancers.
- Understanding the distinct pathways of oncogenic and normal ras p21 is vital for targeted therapies.
Purpose of the Study:
- To investigate the divergence of signaling pathways between oncogenic and insulin-activated normal ras p21 proteins.
- To identify selective inhibitors of the oncogenic ras p21 pathway.
Main Methods:
- Utilized oocyte maturation as a model system.
- Employed a peptide (residues 35-47) from ras p21, azatyrosine, and CGP 41,251 to inhibit oncogenic p21.
- Used anti-p21 antibody Y13-259 and farnesyl transferase inhibitor CVIM to assess pathway inhibition.
Main Results:
- Peptide, azatyrosine, and CGP 41,251 partially inhibited insulin-induced maturation but fully inhibited oncogenic p21-induced maturation.
- Anti-p21 antibody Y13-259 and CVIM completely inhibited both types of maturation.
- Demonstrated shared and distinct elements in the signal transduction pathways.
Conclusions:
- The signaling pathways of oncogenic and normal ras p21 proteins diverge.
- Selective inhibition of the oncogenic ras p21 pathway is achievable.
- Findings support the development of targeted cancer therapies against oncogenic ras p21.
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