Possible involvement of normal p21 H-ras in the insulin/insulinlike growth factor 1 signal transduction pathway.
Expression of a mutant H-ras gene confers a transformed phenotype to rat-1 fibroblasts which is basically independent of exogenous growth factors (GFs). Rat-1 cells induced to express high levels of the normal H-ras gene were also found to display a transformed phenotype. In contrast to cells expressing mutant H-ras, these cells were dependent on GFs. We used this difference in GF dependence to analyze a possible involvement of exogenous GFs in H-ras function. Compared with untransformed rat-1 cells, cells overexpressing normal H-ras displayed an elevated response toward insulinlike growth factor 1 (IGF-1), insulin, and bombesin and an increased sensitivity toward phosphatidic acids. It was found that 8-bromo-cyclic AMP inhibited the responses to all GFs in rat-1 cells but had no effect on mutant-H-ras-transformed cells. In cells overexpressing normal H-ras, 8-bromo-cyclic AMP inhibited the responses to all GFs except those to insulin and IGF-1. This implies that overexpression of normal H-ras in the presence of insulin/IGF-1 is functionally similar to the expression of mutant H-ras, since mutant H-ras can circumvent this block by itself. These and other results strongly suggest a functional linkage between insulin/IGF-1 and normal p21 H-ras.
Burgering
B M
BM
Department of Medical Biochemistry, Sylvius Laboratories, Leiden, The Netherlands.
Snijders
A J
AJ
Maassen
J A
JA
van der Eb
A J
AJ
Bos
J L
JL
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D000242:Cyclic AMP / Q000502:physiology; D004261:DNA Replication / Q000187:drug effects; D015870:Gene Expression; D006133:Growth Substances / Q000502:physiology*; D007328:Insulin / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D015689:Oncogene Protein p21(ras) / Q000502:physiology*; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D017451:Receptors, Somatomedin; D015398:Signal Transduction / Q000502:physiology
D006133:Growth Substances; D007328:Insulin; D011956:Receptors, Cell Surface; D017451:Receptors, Somatomedin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D007334:Insulin-Like Growth Factor I; D000242:Cyclic AMP; D011972:Receptor, Insulin; D015689:Oncogene Protein p21(ras)