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Protective effect of the insulin-like growth factor I receptor on apoptosis induced by okadaic acid
C D'Ambrosio1, B Valentinis, M Prisco
1Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Abstract:
Okadaic acid (OKA), a potent inhibitor of serine phosphatases at concentrations as low as 20-25 nM, induces apoptosis of R- mouse embryo fibroblasts, which are 3T3-like cells devoid of type 1 insulin-like growth factor receptors (IGF-IRs). From R- cells, we have generated (by stable transfection) cell lines with IGF-IR numbers ranging from 0 (R- cells) to >10(6) receptors per cell. The wild-type IGF-IR protects R- cells from OKA-induced apoptosis, its protective effect being exquisitely dependent on the number of receptors. A small increment in wild-type receptor number (from 15 x 10(3) to 22 x 10(3) receptors/cell) is sufficient to change R(-)-derived cells from sensitive to resistant to apoptosis. We have also studied the effect of various mutations of the IGF-IR on its ability to protect R(-)-derived cells from OKA-induced apoptosis. Our data indicate a correlation between protection from apoptosis and the ability of the receptor to respond to insulin-like growth factor I with mitogenesis.
Insights
Okadaic acid induces apoptosis in cells lacking insulin-like growth factor-1 receptors (IGF-IRs). Increasing IGF-IR numbers protects cells from this apoptosis, linking receptor levels to cell survival.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Okadaic acid (OKA) is a potent serine phosphatase inhibitor.
- R- mouse embryo fibroblasts lack type 1 insulin-like growth factor receptors (IGF-IRs) and undergo apoptosis upon OKA treatment.
Purpose of the Study:
- To investigate the role of IGF-IRs in protecting cells from OKA-induced apoptosis.
- To determine the relationship between IGF-IR number and the protective effect against apoptosis.
- To examine how IGF-IR mutations affect protection from OKA-induced apoptosis.
Main Methods:
- Generation of R- cell lines with varying IGF-IR expression levels via stable transfection.
- Treatment of cell lines with Okadaic acid (OKA).
- Assessment of apoptosis induction and IGF-IR function (mitogenesis) in response to insulin-like growth factor I (IGF-I).
Main Results:
- Wild-type IGF-IR confers protection against OKA-induced apoptosis in a dose-dependent manner.
- A modest increase in IGF-IR number (15,000 to 22,000 receptors/cell) significantly shifts cells from apoptosis sensitivity to resistance.
- Receptor protection from apoptosis correlates with the ability of IGF-IR to mediate IGF-I-induced mitogenesis.
Conclusions:
- The number of functional type 1 insulin-like growth factor receptors is critical for protecting cells against Okadaic acid-induced apoptosis.
- IGF-IR-mediated protection is linked to its signaling capacity for mitogenesis.