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Malignant transformation by ras and other oncogenes produces common alterations in inositol phospholipid signaling
T Alonso1, R O Morgan, J C Marvizon
1Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892.
Abstract:
The role of ras proteins in signal transduction was assessed by studying inositol phospholipid metabolism and inositol phospholipid-mediated cellular responsiveness to agonists in cells transformed by ras and other oncogenes. Specific alterations were observed in the inositol phospholipid cycle of ras-transformed fibroblasts, but similar changes were also produced by spontaneous transformation or transformation mediated by either membrane-associated oncogenes, such as src, met, or trk, or cytoplasmic oncogenes, mos and raf; the nuclear oncogenes fos and myc did not produce these changes. The alterations included (i) stimulation of phospholipase A2 activity as indicated by elevated levels of glycerophosphoinositol and nonesterified arachidonic acid and (ii) specific uncoupling between surface receptor-mediated stimulation by platelet-derived growth factor, bombesin, or serum and activation of intracellular phospholipase C. These findings suggest the existence of common biochemical pathways for transformation by cytoplasmic and membrane-associated oncogenes and are not consistent with the hypothesis that 21-kDa ras proteins (p21) are direct or distinct regulatory elements of phospholipase C or phospholipase A2 in inositol phospholipid signal transduction pathways.
Insights
Ras proteins (p21) do not directly regulate phospholipase C or A2 in signal transduction. Oncogene transformation alters inositol phospholipid metabolism similarly, suggesting common pathways, not ras-specific regulation.
Area of Science:
- Molecular Biology
- Cellular Biology
- Oncology
Background:
- Signal transduction pathways are crucial for cellular processes.
- Oncogenes, such as ras, can disrupt normal cell growth and function.
- Inositol phospholipid metabolism plays a key role in cellular signaling.
Purpose of the Study:
- To investigate the role of ras proteins in signal transduction.
- To examine inositol phospholipid metabolism in ras-transformed cells.
- To determine if ras proteins directly regulate phospholipase C or A2.
Main Methods:
- Studied inositol phospholipid metabolism in ras-transformed fibroblasts.
- Assessed cellular responsiveness to agonists.
- Analyzed alterations in phospholipase A2 activity and receptor-mediated activation of phospholipase C.
Main Results:
- Ras transformation altered inositol phospholipid metabolism, similar to other oncogenes.
- Elevated phospholipase A2 activity and uncoupling of phospholipase C activation were observed.
- Nuclear oncogenes (fos, myc) did not induce these specific metabolic changes.
Conclusions:
- Ras proteins (p21) are not direct or distinct regulators of phospholipase C or A2.
- Common biochemical pathways exist for transformation by cytoplasmic and membrane-associated oncogenes.
- Findings challenge the hypothesis of direct ras protein regulation in inositol phospholipid signaling.